Skip to main content

MicroRNAs as the critical regulators of cell migration and invasion in thyroid cancer

Abstract

Thyroid cancer (TC) is one of the most frequent endocrine malignancies that is more common among females. Tumor recurrence is one of the most important clinical manifestations in differentiated TC which is associated with different factors including age, tumor size, and histological features. Various molecular processes such as genetic or epigenetic modifications and non-coding RNAs are also involved in TC progression and metastasis. The epithelial-to-mesenchymal transition (EMT) is an important biological process during tumor invasion and migration that affects the initiation and transformation of early-stage tumors into invasive malignancies. A combination of transcription factors, growth factors, signaling pathways, and epigenetic regulations affect the thyroid cell migration and EMT process. MicroRNAs (miRNAs) are important molecular factors involved in tumor metastasis by regulation of EMT-activating signaling pathways. Various miRNAs are involved in the signaling pathways associated with TC metastasis which can be used as diagnostic and therapeutic biomarkers. Since, the miRNAs are sensitive, specific, and non-invasive, they can be suggested as efficient and optimal biomarkers of tumor invasion and metastasis. In the present review, we have summarized all of the miRNAs which have been significantly involved in thyroid tumor cells migration and invasion. We also categorized all of the reported miRNAs based on their cellular processes to clarify the molecular role of miRNAs during thyroid tumor cell migration and invasion. This review paves the way of introducing a non-invasive diagnostic and prognostic panel of miRNAs in aggressive and metastatic TC patients.

Background

Thyroid cancer (TC) is the most common head and neck cancer that involves 91.5% of all endocrine malignancies. It is the 7th common cause of cancer in females and the 14th among male. Based on the American Cancer Association studies, most of the new TC cases have been diagnosed in females under the age of 65 [1]. The major cause of difference between females and males incidence rates can be related to the estrogen receptors genes polymorphisms in females which can considerably increase the tumor cell proliferation [1, 2].

TC is histopathologically categorized into different subtypes including well-differentiated TC (WDTC), poorly-differentiated TC (PDTC), and undifferentiated anaplastic thyroid carcinomas (ATC). WDTC also contains two subtypes: papillary TC (PTC) and follicular TC (FTC) (Table 1). PTCs are the most common differentiated thyroid carcinomas (80–85% of all thyroid malignancies) [3], while the ATC is the least common and most aggressive type with poor prognosis. FTC is also the 2nd most frequent malignancy originating from follicular cells which is categorized into minimally invasive FTC (MI-FTC) and widely invasive FTC (WI-FTC) [4]. Most of differentiated TC with slow clinical progression causes distant metastasis and reduced survival rate. Tumor recurrence is one of the most important clinical manifestations in differentiated TCs. Different risk factors including age, tumor size, histological features, and metastasis influence the recurrence of differentiated TC [5,6,7].

Table 1 Histopathological classification of thyroid cancer

Environmental factors, lifestyles, or a combination of these factors are supposed to be possible causes for the raising trend of TC incidence [8]. Gender, weight, diabetes mellitus, ionizing radiation, pregnancy, genetic factors, thyroid disorders, hormones, and dietary pattern are among the risk factors of TC [9,10,11]. Various molecular processes such as genetic or epigenetic modifications and non-coding RNAs are involved in TC progression and metastasis [3]. The epithelial-to-mesenchymal transition (EMT) is an important biological process during tumor invasion and migration in which the epithelial cells can lose their cell-cell adhesion and turn into mesenchymal phenotype. It affects the initiation and transformation of early-stage tumors into invasive malignancies [12]. EMT is triggered by the down regulation of epithelial markers like CDH1 and up regulation of mesenchymal markers like vimentin and CDH2 [13]. EMT can be the basic cause of tumor invasion and migration [14]. A combination of transcription factors, growth factors, signaling cascades, epigenetic regulations and tumor environment affect the thyroid cell migration and EMT process [14]. There is a correlation between TC poor prognosis and genetic alterations in EMT-related genes and transcription factors. EMT-related factors suppress the expression of E-cadherin (E-CAD) and are related to tumor progression, local invasion, and metastasis [15, 16]. Molecular mechanisms of EMT and cell migration are regulated by WNT, TGFβ, MAPK, and phosphatidylinositol-3-kinase (PI3K) pathways [14, 17]. Some of the essential transcription factors such as Twist, Snail1-2, and ZEB1-2 are the main triggers of the EMT process [18,19,20,21]. WNT, NOTCH, and TGF-β are also the major signaling pathways to activate the EMT-promoting transcription factors [22, 23]. Snail-2 is positively regulated by NOTCH signaling that results in EMT induction following the CDH1 inhibition [24].

MicroRNAs (miRNAs) are important molecular factors involved in tumor metastasis by regulation of EMT-activating signaling pathways [25]. Specific patterns of miRNA expression have been identified in thyroid carcinomas [26,27,28]. MiRNA profiling is widely being introduced as biomarkers in a variety of diseases which can be used as prognostic and predictive factors in the clinical research [29]. Various studies have demonstrated that miRNAs deregulation plays a pivotal role in tumor cell invasion and migration [30, 31]. Different miRNAs have been participated in the signaling pathways of thyroid tumor metastasis and migration which could be applied as novel biomarkers for treatment and early stage diagnosis [32]. Since, the miRNAs are sensitive, specific, and non-invasive; they can be suggested as efficient and optimal biomarkers of tumor invasion and metastasis. The miRNAs expression can be recognized in body fluids and tissues which are associated with developmental stages, tissues, and external stimulation. Circulating miRNAs in body fluids are frequently used as non-invasive tumor biomarkers [33, 34]. There are different miRNA quantification methods including sequencing, hybridization, and amplification based methods. NGS, microarray, and real-time PCR have been widely employed to discover circulating miRNAs [35]. Bead-based flowcytometry assays were also developed to solve the cross-hybridization challenge of miRNAs in the microarray procedures [33, 36]. Some other amplification methods such as rolling circle amplification (RCA), strand displacement amplification (SDA), and loop-mediated isothermal amplification (LAMP) have been also employed to assess the miRNAs functions [37]. Liquid biopsy has minimal invasion for the assessment of tumor profile in comparison with tumor biopsy. However, this method has some limitations including short half-life of circulating miRNAs, low concentration, and contamination with normal cells [38,39,40]. In present review, we have summarized all of the miRNAs that have been involved in thyroid tumor cells migration and invasion to pave the way of introducing a non-invasive diagnostic and prognostic panel of miRNAs in TC. We have categorized all of the reported miRNAs based on their cellular processes to clarify the molecular role of miRNAs during thyroid tumor cell migration and invasion (Table 2).

Table 2 All of the microRNAs associated with tumor cell migration and invasion in thyroid cancer

MiRNAs involved in regulation of PI3K/AKT signaling

Cell migration is a critical process in normal and tumor cells. The PI3K kinases regulate cell migration through directly or through activation of other signaling pathways [124]. MiRNAs have critical roles in regulation of thyroid tumor cell migration through PI3K/AKT signaling (Fig. 1). AKT is a component of the PI3K/AKT pathway involved in cell proliferation, programmed death, migration, invasion, and metabolism [125,126,127,128]. A significant inverse correlation has been reported between miR-497 and AKT3 in PTC. MiR-497 also inhibited PTC cells migration and invasion through AKT3 suppression [41]. The tumor-suppressive role of miR-145 has been suggested in various cancers. Moreover, miR-145 has been revealed to participate in cell differentiation and proliferation [129, 130]. It has been reported that there were significant reduced levels of miR-145 expressions in PTC, PDTC, and ATC compared with normal thyroid tissue. MiR-145 targeted the AKT3, N-cadherin, and HIF1α during thyroid cancer progression. Although, there were increased serum levels of miR-145, it was under expressed in tissue samples [42]. MiR-217 expression has been also revealed to be significantly reduced compared with normal tissues in TC patients. The miR-217 down regulation was also associated with clinical stage and lymphatic metastasis. MiR-217 also suppressed the growth of the tumors in vitro and in vivo through the AKT3 targeting in TC [43]. MiR-203 has a cardio protective role through inhibiting the PI3K/AKT in diabetic cardiomyopathy [131]. It has been reported that the miR-203 up regulation and AKT3 down regulation reduced tumor cell migration, increase E-cadherin, and reduce vimentin expression levels in PTC cells [44]. A significant miR-338-3p up regulation in TC tissues in comparison with normal margins was inversely correlated with the clinical stage and lymphatic metastasis. The miR-338-3p also significantly suppressed the cell migration of TC cells and repressed tumor development in vivo by targeting AKT3 [45]. Another study has been observed that there was miR-29a down regulation in PTC tissues which was inversely correlated with TNM stage, tumor size, and lymphatic metastasis. It also suppressed PTC cell migration and invasion by targeting AKT3 [46]. AKT2 is an oncogenic serine/threonine kinase with SH2 domains capable of phosphorylating downstream targets. The up regulation of Let-7a expression has been revealed to significantly inhibit the PTC migration and invasion by targeting AKT2. There was also Let-7a down regulation in PTC compared with healthy tissues [47]. AKT is a member of AGC family regulated by PDPK1 that is involved in insulin and growth factors signaling [132]. PDPK1 has a significant role in regulation of AGC protein kinases family, which controls cell proliferation, growth, and metabolism [133]. MiR-718 is a critical negative regulator for the PTC cell proliferation and migration through PDPK1 targeting [48].

Fig. 1
figure 1

Role of miRNAs in thyroid tumor cell migration via regulation of PI3K/AKT and chemokine signaling pathways. (Created with BioRender.com)

PI3K family is involved in regulation of cellular growth, proliferation, and glucose homeostasis. MiR-125b has been reported to be significantly down regulated in the ATC tissues and cell lines. It directly targets PIK3CD and inhibits the migratory and invasive capacity of tumor cells via PI3K-Akt-mTOR cascade. While up regulated miR-125b significantly inhibited the invasive and migratory behavior of cells, its knockdown promoted the invasion and migration of ATC cells [49]. Another group has been shown that there was miR-363-3p under expression in TC tissues and cell lines which was inversely associated with clinical stage and lymph node metastases. It significantly repressed migratory and invasive behaviors of PTC cells and prevented in vivo tumorigenesis. There was a significant negative relationship between PIK3CA and miR-363-3p expression, indicating PIK3CA as a target of miR-363-3p in PTC [50]. PPM1E is a serine/threonine-protein phosphatase that has important role in cell proliferation by regulation of AMPK-mTOR signaling [134]. There was LINC01087 up regulation and miR-135a-5p down regulation in TC tissues and cell lines compared with normal margins and cells. LINC01087 induced TC cell migration via miR-135a-5p/PPM1E axis [51]. HnRNPA1 as a substrate for S6K2 in AKT/mTOR signaling has a pivotal anti-apoptotic function [135]. CircTIAM1 induced PTC cell migration through the miR-646/HNRNPA1 axis [52]. GALNT7 induces cell proliferation and migration via the activation of EGFR/PI3K/AKT pathway. MiR-30b-5p down regulation was correlated with poor clinicopathological features in PTC. MiR-30b-5p inhibited PTC cell proliferation and migration by GALNT7 targeting [53].

MiR-141 acts as an anti-oncogene by targeting EphA2, E2F3, ZEB2, Tiam1, KEAP1, and SOX17 [136,137,138,139,140,141]. IRS2 belongs to the IRS protein family that interacts with the SH2-domain-containing proteins, primarily PI3K during insulin signal transduction [142, 143]. It is a multifunctional oncogene that regulates cell proliferation, invasion, and EMT [144,145,146]. It has been shown that miR-141 inhibited cell migration and invasive capability of thyroid tumor cells. It also triggered cell death, and repressed tumor growth by IRS2 targeting. Moreover, miR-141 down regulation was significantly correlated with TNM stage and lymph node involvement [54]. Another study also showed that the miR-766 inhibited the malignant activity of PTC cells through IRS2 suppression. There was a significant miR-766 down regulation in PTC tissues and cell lines which was correlated with TNM staging and lymph node involvement [55].

Succinate dehydrogenase (SDH) is a crucial enzyme in the mitochondrial citric acid cycle [147,148,149]. This enzyme is involved in succinate to fumarate oxidation and electron transport [150, 151]. SDHB deregulation is involved in oxidative phosphorylation in several cancers [147, 152, 153]. The SDHB dysfunction elevates TGFβ-mediated colorectal cancer invasion and metastasis via the SNAIL1-SMAD3/4 transcriptional repressor complex [154]. It has been reported that there was increased levels of miR-96-3p expressions in PTC tissues in comparison with normal margins which was associated with advanced tumor stage. The miR-96-3p up regulation increased tumor cell invasion and TC metastasis by regulating SDHB/AKT/mTOR pathway [155]. It has been observed that there were decreased levels of miR-215 expressions in PTC tissues that were correlated with tumor size and invasion. In vivo and in vitro studies have also shown that the miR-215 up regulation significantly repressed the proliferation and metastasis of PTC cells through targeting ARFGEF1. MiR-215 suppressed PTC metastasis by regulating the AKT/GSK-3β/Snail cascade and ARFGEF1 targeting [56].

MIF is a pivotal pro-inflammatory cytokine during tumor progression and growth by AKT activation [156]. It has been shown that there was miR-451a down regulation in PTC samples which was significantly correlated with the aggressive PTC and advanced TNM stage. There was also an inverse association between the levels of MIF and miR-451a expressions that suggested the MIF as the target of miR-451a [57]. The miR-146b is correlated with tumor aggressiveness and poor prognosis of PTC [157]. MiR-146b up regulation enhances cell migration, EMT, and metastasis [158]. It is involved in regulation of PTEN/PI3K/AKT pathway during thyroid tumor aggressiveness. PTEN suppression by miR-146b revealed some information about the processes and positive feedback loops mediating the PI3K pathway activation in thyroid tumorigenesis. MiR-146b also reduced pSTAT3 and E-cadherin levels. TWIST as an important EMT factor, may mediate the effect of miR-146b on invasion and migration since its expression level is up regulated in cells with miR-146b up regulation. In contrast, E-cadherin is down regulated in cells with miR-146b overexpression [58]. TRIM14 is involved in regulation of PI3K/AKT pathway by the PTEN inhibition [159]. MiR-671-5p inhibited the PTC cell migration by TRIM14 targeting [59]. CircWDR27 increased PTC cell migration by regulation of the miR-215-5p/TRIM44 axis [60]. There was an inverse association between the levels of LINC00958 and miR-627 expressions in PTC samples. LINC00958 increased PTC cell migration by miR-627 sponging and TRIM44 up regulation [61].

MiRNAs involved in regulation of WNT and Hippo signaling pathways

WNT/b-catenin is a pivotal signaling pathway involved in cell proliferation, polarity, embryogenesis, and tumor progression [160,161,162]. It participates in the neoplastic transformation from low grade to high-grade or ATC with poor prognosis [163]. MicroRNAs are critical factors in thyroid tumor cell migration by regulation of WNT signaling pathway (Fig. 2). It has been revealed that there were correlations between miR-3619-3p up regulation, extra thyroidal extension, and lymphatic metastases in PTC tissues. The miR-3619-3p also promoted the migratory and invasive capability of PTC cells through increased b-catenin mRNA stability [62]. LRP6 is a co-receptor of the WNT signaling, which induces the WNT target genes by increased rate of b-catenin nuclear transport [164, 165]. It has been shown that the miR-126 up regulation suppressed PTC cells migration and in vivo tumor growth through LRP6 suppression. There was also a significant miR-126 down regulation in PTC tissues and cell lines which was significantly associated with lymph node involvement, tumor size, and TNM stage. Moreover, suppression of LRP6 by miR-126 resulted in down regulation of CCND1, MMP7, and C-myc [63]. Another group observed that the miR-381-3p was associated with PTC metastasis through LRP6 down regulation. There were also significant decreased miR-381-3p expression in PTC tissues and cell lines [64]. WNTs are secretory glycoproteins with pivotal roles during cell differentiation, proliferation, and migration [166]. WNT5A is a positive regulator of classical or non-classical WNT pathways. It has been reported that there was a miR-26a-5p down regulation in PTC cells and tissues compared with healthy thyroid cells and tissues. It also inhibited the PTC cell growth, invasion, and metastasis via WNT5a suppression [65]. MiR-329 is reported to be down regulated in PTC samples and cell lines compared with normal margins and healthy cell lines. It also inhibited the cell migration, invasion, and in vivo tumor growth via WNT1 suppression. Moreover, there was an inverse correlation between the levels of miR-329 and WNT1 mRNA expressions in PTC samples [66].

Fig. 2
figure 2

Role of miRNAs in thyroid tumor cell migration via regulation of WNT signaling pathway. (Created with BioRender.com)

Forkhead Box N3 (FOXN3) has a crucial role as a transcriptional repressor in cell cycle regulation and carcinogenesis [167]. It has been reported that the miR-574-5p mediated TC cell proliferation and migration through the Wnt/β-catenin pathway by targeting FOXN3. MiR-574-5p silencing prevented the cell proliferation and migration, while enhanced apoptosis in TC [67]. SCAI is a tumor suppressor that inhibits cell migration through β1-integrin and WNT signaling suppression [168, 169]. Abnormal miR-1270 up regulation has been revealed in human PTC cell lines and tumors. Down regulation of miR-1270 suppressed the PTC tumor cells migration and in vivo transplantation. It has been shown that the miR-1270 was involved in PTC progression through SCAI targeting [68]. MiR-625-3p is an oncogene in various cancers that induce the tumor cell proliferation, migration, and drug tolerance [170, 171]. AEG-1 is correlated with PTC metastasis by up regulations of MMP2 and MMP9 [172]. It has been reported that there was miR-625-3p up regulation in PTC tissues compared with normal margins. MiR-625-3p up regulation enhanced the migratory and invasive capability of SW579 and TPC-1 cell lines. Besides, AEG-1 was up regulated by miR-625-3p in SW579 and TPC-1 cell lines. AEG-1 up regulation also enhanced cell migration, and activated the WNT and JNK signaling pathways. Moreover, there were significant up regulations of BAX, CASP3, and CASP9 following miR-625-3p suppression in SW579 and TPC-1 cells. Therefore, miR-625-3p enhanced TC cell migration and invasion by AEG-1 up regulation and triggering WNT and JNK pathways [69]. Another group showed the negative role of miR-564 on PTC migration and invasion via AEG1 inhibition. There was also miR-564 under expression in PTC tissues and cell lines which was significantly correlated with lymph node involvement and the TNM stage [70].

YAP1 (yes-associated protein 1) is one of the key effectors of Hippo signaling pathway which is involved in regulation of OCT4 and SOX2 to promote self-renewal capability [173]. It has been reported that there was miR-205 down regulation in PTC samples. It also inhibited the Hippo signaling cascade by targeting YAP1 and suppressed TC cell migration and invasion [71]. SNHG15 is a competitively endogenous RNA (ceRNA) that regulates the Hippo signaling pathway through miR-200a-3p sponging in PTC [174]. It has been shown that there was miR-510 up regulation in TC tissues and cell lines compared with the healthy thyroid tissues and cell lines. There was an inverse association between SNHG15 and miR-510-5p expression. The miR-510-5p also promoted the TC cell migration and invasion via SNHG15 targeting. Moreover, miR-510-5p up regulation has been reported in advanced stage tumors with lymphatic metastasis [15]. CRABP2 is a positive regulator of EMT by inhibition of Hippo pathway [175]. LINC01816 increased TC cell migration and EMT process via miR34c5p/CRABP2 axis [72].

MiRNAs involved in regulation of TGFβ signaling pathway

TGFβ1 is a cytokine that functions as a tumor suppressor in the early stages of tumor progression and as an oncogene during advanced stages of tumors [176, 177]. It regulates the tumor cell migration and invasion by Smad-dependent or Smad-independent signaling pathways [176, 178]. It has also a critical role in EMT, characterized by E-cadherin and cytokeratin down regulations and increased expressions of N-cadherin and vimentin [176, 179, 180]. MicroRNAs are involved in TC cell migration through the regulation of TGFβ signaling (Fig. 3). It has been reported that there was miR-663 down regulation in PTC cases which was correlated with extra thyroidal extension, age, tumor size, and poor prognosis. It also reduced PTC cell invasion, migration, and EMT via TGFβ inhibition. The overexpressed-miR-663 PTC cell lines had E-cadherin over expression, while N-cadherin, vimentin, MMP-2, and MMP-9 down-regulations [73]. MiR-146b-5p is involved in regulation of TGF-b signal transduction through suppressing SMAD4 in PTC [181] and enhancing tumor metastasis through ZNRF3 targeting [158]. It has been shown that there was miR-146b-3p up regulation in PTC samples. It also promoted cell migration and invasion via NF2 suppression [182]. Another study has been shown that miR-146b-5p was involved in tumor cell migration through SMAD4 targeting in PTC [74]. PARD protein family regulates the polarity, migration, and cell proliferation [183]. Cell polarity disruption in various cancers has been suggested to be influenced by PARD impairment. Interaction of PARD3 and TGF-β may alter the PARD complex, leading to a neoplastic transformation [184]. PARD3 prevented the actin polymerization triggered by Tiam1-Rac1 and thus stabilized cell-cell contacts and repressed the tumor cells migration. It has been reported that miR-483 up regulated the Tiam1-Rac1 signals through PARD3 down regulation. Although, PARD3 inhibited the TGF-β1-mediated EMT and invasion, it’s down regulation via miR-483 stimulated Tiam1-Rac1 and facilitated EMT and migration of TC cells. Moreover, MiR-483 and PARD3 have been reported to be up regulated and down regulated in thyroid tumor samples, respectively [75].

Fig. 3
figure 3

Role of miRNAs in thyroid tumor cell migration by regulation of TGFβ and cytokine signaling pathways. (Created with BioRender.com)

MiRNAs involved in regulation of cytokines

Cytokines have a pivotal role in TC cell migration and metastasis that can be regulated by the microRNAs (Fig. 3). IL-22 is a member of IL-10 family cytokines that is mainly produced by activated Th17 or Th22 cells [185,186,187]. It is involved in antimicrobial defense in the gastrointestinal tract, tissue regeneration, and injury protection [188,189,190]. It is correlated with tumor progression and metastasis in breast, lung, and gastric cancers [191,192,193]. SOX17 belongs to the SOX family of transcription factors and has a crucial role in human tumorigenesis [194]. It has been found that the IL-22 induced miR-595 expression which resulted in SOX17 down regulation and increased PTC cell migration [195]. The chemokine superfamily is small and structurally related proteins, capable of binding and interacting with G-protein coupled receptors, leading to cytoskeletal rearrangement and directional cell migration [196]. SOCS1 is a negative regulator of cytokine signal transduction [197]. The miR-155 up regulation was reported among ATC tissues. There were also correlations between miR-155 expression and extra thyroidal invasion. Moreover, Overexpression of miR-155 enhanced tumor progression by SOCS1 suppression [76]. IL-23 is a type 1 cytokine which is a member of the IL-6 superfamily [198]. It has been shown that IL-23 regulated the migratory and invasive behavior of TC cells through miR-25/SOCS4 signaling. MiR-25 enhanced the TC migration via targeting SOCS4. Moreover, it regulates the expression of IL-23-associated SOCS4 in TC cells [77].

Chemokines and their receptors have critical roles in tumor cell migration and metastasis [199]. MicroRNAs are involved in regulation of TC cell migration by chemokine targeting (Fig. 1). It has been reported that there was miR-126 down regulation in TC tissues and cell lines. It also reduced tumor cell migration and invasion via CXCR4 targeting [78]. DUXAP8 induced PTC cell migration and proliferation through the regulation of miR-223-3p/CXCR4 axis [79]. CXCL12 is a potent chemo attractant for hematopoietic cells and essential for the migration of tumor cells [200]. It binds with its CXCR4 receptor to activate the PI3K/AKT and ERK signaling pathways leading to cell migration [201]. A significant down regulation of miR-137 has been revealed in PTC tissues which were negatively associated with tumor TNM classification and lymph node metastasis. It also inhibited PTC cell migration by targeting CXCL12 [80]. There was an inverse association between the levels of miR-455-5p and circPVT1 that was correlated with MTC prognosis. MiR-455-5p suppressed EMT and invasion in MTC cells by CXCL12 targeting [81]. It has been observed that there were decreased levels of miR-1 expressions in benign and malignant thyroid neoplasms compared with healthy thyroid tissue. MiR-1 regulated the TC cell migration through CXCR4, SDF-1, and MET suppression [82]. CXCL16-CXCR6 interaction is crucial during tumor progression of the aggressive cancers [202]. It has been reported that there was miR-873-5p down regulation and CXCL16 up regulation in PTC samples that introduced CXCL16 as a target of miR-873-5p. MiR-873-5p also inhibited PTC cells migration by targeting CXCL16 [83].

MiRNAs involved in regulation of kinases

BDNF is a member of neurotrophin family of tyrosine kinase receptors which is involved in regulation of PI3K/AKT, RAS/ERK, PLC/PKC, and JAK/STAT signaling pathways during tumor progression [203]. It has been shown that there was miR-497 down regulation in TC samples compared with normal margins which was inversely associated with lymph node involvement and advanced clinical stage. It also suppressed cells colony-forming, migration, and in vivo tumor growth through BDNF targeting and PI3K-AKT inhibition [84]. MET belongs to the tyrosine kinase receptor protein family that regulates cell growth. It has been reported that there were circ-0079558 and MET up regulations in PTC tissues and cell lines. Circ-0079558 promoted the PTC cell proliferation and migration, while reduced apoptosis via miR-26b-5p/MET/AKT axis [85]. ERBB2 is a tyrosine kinase receptor associated with tumor progression [204]. It has been reported that the miR-375 was down regulated in PTC tissues and cell lines. It also suppressed the proliferative capability of PTC cell lines by apoptosis induction. Moreover, miR-375-mimic transfection significantly reduced PTC cell migration and invasion through ERBB2 suppression [86]. FGF2 is a ligand of FGFR that is associated with tumor cell migration and invasion [205]. It has been reported that there were significant miR-195 down regulation in PTC tissues and cell lines. It also suppressed PTC cell migration through CCND1 and FGF2 suppression. Moreover, miR-195 enhanced the phosphorylation of β-catenin which inhibited WNT signaling in PTC [206]. ATC is an aggressive, malignant neoplasm, distinguished by poor prognosis [207,208,209]. EGFR is a tyrosine kinase up regulated in the majority of ATC samples [210]. The EGF is produced by the thyroid gland and promotes the migratory and invasive behaviors of thyroid cancer cells [209, 211,212,213,214]. It has been shown that the EGF/EGFR activation reduced E-cadherin and up regulated vimentin. EGF/EGFR pathway modulated the aggressive behaviors of SW1736 cells by regulating miR-200 in which, EGF reduced miR-200, increased Rho/Rock activity, and increased EMT in TC cells [215]. VEGFA is a tyrosine kinase receptor involved in angiogenesis. CircPVT1 promoted the PTC cell migration by miR-195 sponging and subsequent VEGFA up regulation [87]. Janus kinases (JAK) are a class of tyrosine kinases involved in cell growth, differentiation, and apoptosis. It has been reported that the miR-520a-3p inhibited the JAK-STAT signaling by JAK1 suppression which inhibited EMT and migration of PTC cells. The miR-520a-3p up regulation or JAK1 knockdown resulted in under expression of JAK1 and EMT-linked markers such as E-cadherin and vimentin in PTC tissues [88].

ROCK1 is a serine/threonine kinase belonging to the Rho-associated kinase family (ROCK) that participates in various cellular processes such as mitochondrial fission, cell signaling, and cytoskeletal organization [216, 217]. It has been shown that there were significant correlations between miR-361-5p down regulation, lymphatic metastasis, and TNM stage in PTC cases. The miR-361-5p up regulation also inhibited the migration and invasion of TPC-1 cells. Besides, miR-361-5p diminished in vivo tumor development in PTC xenografts. Moreover, the miR-361-5p under expression was correlated with poor prognosis in PTC cases. There was an inverse correlation between the expression level of ROCK1 and miR-361-5p which showed miR-361-5p prevented PTC cells migration by ROCK1 targeting [89]. Another group also showed that the miR-150-5p inhibited PTC cell migration through ROCK1. There was a reduced levels of miR-150 expression in PTC tissues and cell lines compared with controls. The miR-150-5p down regulation was also correlated with TNM stages and lymph node metastasis [90].

Sphingolipids consist of a wide variety of hydrophobic molecules including Ceramide, Sphingoid, Ceramide Phosphates, and Sphingoid Base Phosphates [218]. The proliferative and invasive behavior are associated with dynamic equilibrium between ceramide phosphates and sphingoid phosphates [219]. Sphingosine kinases (SPHKs) involve two different variants, including SPHK1 and SPHK2 [220, 221]. SPHK1 catalyzes S1P (Sphingosine 1-phosphate) formation from pro-apoptotic sphingolipid [219]. It has been shown that there were decreased levels of miR-128 expressions in PTC, FTC, and TC cell lines. The miR-128 reduced TC cell migration and invasion via targeting SPHK1. Besides, the up regulation of miR-128 significantly induced cell death in TC cell lines through CASP-3 up regulation. MiR-128 up regulated and down regulated the E-cadherin and N-cadherin, respectively [91]. Another group showed that the miR-577 up regulation suppressed PTC cells migration and invasion through SPHK2 suppression. There were also significant miR-577 down regulations in PTC tissues and cell lines [92]. MiR-613 significantly inhibited the PTC cell migration, invasion, and in vivo growth by targeting SPHK2. Moreover, there was miR-613 down regulation in PTC cell lines and tissues [93].

CARMA1 is a member of membrane-associated guanylate kinase family that functions as membrane scaffolds. It has a vital function in NF-kB regulation which is induced by antigen-receptor in T and B lymphocytes [222, 223]. CARMA1 is phosphorylated by protein kinase C-theta (PKC-θ) following T cell receptor and CD28 binding, leading to the formation of an active complex that consists of CARMA1 as well as downstream signaling scaffolding adaptor proteins, including BCL10 and MALT1 [224, 225]. Subsequently, these molecules are recruited into the lipid micro-domains at the immune synapse, which results in activating KK complex and NF-kB [226]. It has been reported that the CARMA1 was targeted and down regulated by miR-539, thereby inhibiting thyroid tumor cell metastasis. Therefore, miR-539 is a modulator of TC cell migration and invasion by targeting CARMA1 [94].

MAPK1 is a serine/threonine kinase involved in MAP/ERK signaling pathway. MiR-675 down regulation has been observed in PTC tissues and cell lines that were significantly associated with lymphatic metastases and the TNM stage. It also inhibited PTC cell migration and in vivo growth through MAPK1 regulation [95]. The p21-activated kinase (PAK1) is also a serine/threonine kinase that regulates cytoskeletal remodeling, directional motility, metastasis, and cell cycle progression. It has a pivotal role in interaction between Rho GTPases and cytoskeletal reorganization [227]. The miR-7 down regulation has been shown in TC tissues which were correlated with stage. It also inhibited TC cells migration and invasion through targeting PAK1 [96]. RAC1 as a Rho GTPase is involved in cell proliferation, adhesion, and migration [228, 229]. RAC1/PAK1 signaling is associated with high glucose-induced podocyte EMT through β-catenin and Snail induction [230]. It has been reported that there was miR-101 down regulation in PTC samples compared with normal margins. It also repressed PTC cell invasion and migration through RAC1 targeting [97].

MiRNAs associated with transcriptional regulation and transcription factors

Signaling pathways mainly exert their role in regulation of tumor cell migration by specific transcription factors. It has been shown that the miRNAs have key roles in thyroid tumor cell migration and EMT by regulation of transcription factors (Fig. 4). High-mobility group-A2 gene (HMGA2) is a non-histone chromatin protein that regulates the chromatin remodeling to induce or suppress transcriptional enhancer activity through binding with AT-rich DNA sequences [231]. HMGA2 has a vital role in tumor growth through regulation of EMT and metastasis [232, 233]. It has been reported that there was significant decreased levels of let-7b in PTC cell lines and tissues. Let-7b inhibited PTC cell migration and invasion through HMGA2 targeting [98]. HMGB1 is also an important chromatin binding protein that interacts with transcription factors and histones to regulate the chromatin remodeling and transcription [234]. It has been reported that the let-7e suppressed PTC migration through HMGB1 targeting [99]. SIRT1 is a NAD-dependent deacetylase involved in regulation of cell-cycle, death, and tumor metastases through MYC, TP53, and NF-κB [235, 236]. It inhibits ovarian tumor cell migration and invasion via HMGB1 deacetylation and down regulation [237]. It has been reported that there was miR-212 down regulation in TC tissues and cell lines which was associated with lymphatic metastasis and clinical stage. It also inhibited cell proliferation, migration, and in vivo growth through SIRT1 targeting [100].

Fig. 4
figure 4

Role of miRNAs in thyroid tumor cell migration and EMT by regulation of transcription factors. (Created with BioRender.com)

ZEB1 and ZEB2 are two E-box-binding transcription factors associated with tumorigenesis [238]. These transcription factors are crucial regulators of the transcription repressor network, which inhibit multiple key epithelial polarity regulators implicated in EMT and invasion [239, 240]. It has been reported that there was miR-144 down regulation in TC. The miR-144 suppressed migration of thyroid tumor cells through targeting ZEB1 and ZEB2 [101]. Another reports also showed that the miR-429 and miR-335 suppressed TC cell migration through ZEB1 and ZEB2 targeting, respectively. Moreover, there were miR-429 and miR-335 down regulations in TC samples and cell lines [102, 103]. Non-coding RNAs (ncRNAs) include long non-coding RNAs (lncRNAs), miRNAs, and Circular RNAs (circRNAs) [241,242,243]. Intracellular circRNAs suppress the miRNA by sponging and binding to the microRNA response element (MRE) [244]. It has been observed that there was circNUP214 up regulation of in PTC in comparison with normal margins. It also induced tumor cells migration and invasion through miR-145 sponging which resulted in ZEB2 up regulation [245]. There was significant circVANGL1 up regulation in PTC tissues that was associated with poor prognosis. CircVANGL1 promoted PTC cell migration and EMT process miR-194 sponging and ZEB1 up regulation [104]. TMPRSS4 is a serine protease associated with tumor cells migration and adhesion by EMT promotion through SIP1/ZEB2 induction [246]. There were reduced levels of miR-1258 in PTC cell lines. The miR-1258 suppression also increased the PTC cell migration and invasion via TMPRSS4 regulation [247].

E2F7 has been widely recognized as a transcriptional repressor of promoters with E2F consensus sequence [248]. It acts as a critical component of the inhibitory loop which is needed to switch off the transcription of E2F-driven G1/S target genes during cell cycle [249]. It has been shown that there was miR-30a down regulation in PTC cells. It also inhibited the PTC cell migration by targeting E2F7 [105]. Yin Yang 1 (YY1) is belonged to the GLI-Kruppel family of zinc-finger transcription factors involved in various cellular processes such as embryogenesis, cell proliferation, cell death, and DNA repair [250]. It has been reported that there was miR-544 down regulation in ATC tissues. It also suppressed tumor metastasis by targeting YY1. The YY1 knockdown repressed cell viability and proliferation and substantially reduced ATC cell migration and invasion [106]. SOX11 is a developmental transcription factor involved in neurodevelopment, neural cell survival, and neurite outgrowth [251]. It has been reported that the miR-211-5p suppressed TC cells migration and invasion by SOX11 targeting [107]. There was circ_0039411 up regulation in PTC tissues and cell lines in comparison with normal margins and cells. Circ_0039411 increased PTC cell migration through the regulation of miR-423-5p/SOX4 axis [108].

EZH2 belongs to the Polycomb-group (PcG) family that is involved in transcriptional repression by histone methylation and chromatin condensation. MiR-25 and miR-30d prevented ATC cell proliferation and colony formation through G2/M arrest. It has been observed that there were inverse correlations between EZH2 protein levels and miR-25 and miR-30d expressions in ATC specimens. MiR-25 and miR-30d had a crucial role in ATC progression through EZH2 targeting [109]. FOXA1 as a transcriptional activator is belonged to the forkhead family of DNA-binding proteins. It has been shown that there were reduced expression levels of miR-132 in TC tissue samples and cell lines, in which the miR-132 inhibited TC cell migration and invasion by suppressing FOXA1 [252]. FOXE1 is also a member of forkhead transcription factors that acts as an important factor during thyroid morphogenesis. It enables polarized epithelial cells to transfer into the cellular matrices, which is required for the tumor invasion and metastasis. It has been observed that the miR-524-5p modulated the PTC cell invasion, migration, and proliferation through FOXE1 and ITGA3 suppression [110].

MRTFA is a transcriptional coactivator involved in cytoskeletal dynamics during cell migration. It has been reported that there was MRTFA up regulation in ATC tissues in comparison with primary tumor tissue. MiR-206 suppressed ATC cells migration through MRTFA targeting [111]. LMO4 is a transcription factor involved in regulation of cell proliferation. There was significant circLDLR up regulation in PTC tissues and cell lines. Knockdown of circLDLR reduced PTC cell migration, while promoted apoptosis by miR-637/LMO4 axis [112].

MiRNAs involved in regulation of membrane associated and extra cellular factors

RAP1B is a member of RAS-family GTPases that has a vital role in cell proliferation, migration, and invasion. As a membrane associated GTPase, it regulates integrin-mediated signaling. It has been reported that there were significant reduced levels of miR-206 expressions in TC tissues and cell lines compared with healthy tissues. The miR-206 also significantly decreased TPC-1 migration through RAP1B targeting [113]. SLC7A5 is a membrane transporter involved in thyroid hormones transportation [253]. ADAM9 belongs to the ADAM family, which has a crucial role in the shedding of membrane-bound proteins [254]. It has been shown that the miR-126-3p suppressed TC cell proliferation, migration, and distant metastasis through SLC7A5 and ADAM9 targeting. Moreover, there was a significant correlation between miR-126-3p down regulation, aggressiveness, tumor size, local invasion, and recurrence [114].

ATC has a survival rate of fewer than six months following diagnosis and is one of the deadliest malignancies [255, 256]. More than two-thirds of ATC patients suffer from locally advanced and metastatic ATC [256, 257]. LOX protein belongs to the amine oxidases family involved in tumors progression [258]. As an ECM remodeling enzyme, LOX is essential for the lysine deamination in collagen and elastin. Although, the ECM modulation has been regarded as the main role of LOX, it also participates in regulation of migration, adhesion, and gene transcription [259,260,261]. It has been reported that there were miR-30a down regulations in ATC samples which was correlated with aggressive TC and increased mortality. It also inhibited ATC cell migration and invasion via LOX suppression [115]. Transgelin-2 (TAGLN2) is an actin-bundling protein involved in regulation of cell migration. There was significant miR-613 down regulation in PTC tissues that was correlated with lymph node metastasis. MiR-613 inhibited PTC cell invasion and EMT via TAGLN2 targeting [116]. Glutathione peroxidase 4 (GPX4) is a phospholipid hydroperoxidase that protects membranes toward the lipid peroxidation. CircKIF4A promoted the PTC cell migration while inhibited ferroptosis by miR-1231 sponging and subsequent GPX4 up regulation [117].

MiRNAs involved in apoptosis and protein degradation

XIAP belongs to the family of apoptosis inhibitor proteins. It has been reported that the miR-618 over expression repressed ATC cell migration and invasion by targeting XIAP [118]. B-cell lymphoma 2 (BCL-2) belongs to the BCL-2 family that either inhibits or induces apoptosis. It has been shown that there was significant miR-15 up regulation in TC cells. It enhanced the MDA-T35 apoptosis and was also correlated with BCL-2 suppression. Migration assay confirmed the inhibitory role of miR-15 on MDA-T35 cells migration [119]. TP73 belongs to the p53 protein family that is involved in cell cycle and apoptosis regulation. CASC7 suppressed the PTC cell proliferation and migration by miR-34a-5p sponging and TP73 up regulation [120].

PSMD10 is one of the components of 26 S proteasome that negatively regulates tumor progression [262]. It has been reported that there was a significant reduced levels of miR-214 in PTC tissues and cells. It also suppressed PTC cell migration and EMT via PSMD10 targeting. Moreover, miR-214 down regulation was associated with lymph node involvement, tumor size, and TNM stage. Down regulation of PSMD10 also suppressed the Akt/GSK-3β/b-catenin cascade in PTC cells [121]. SMURF1 functions as an ubiquitin ligase that participates in viral autophagy, embryogenesis, and bone homeostasis [263,264,265]. It has been reported that there were miR-4319 down regulations in TC tissues and cell lines which were correlated with tumor size, lymphatic metastasis, and TNM clinical stage. The miR-4319 also repressed the TC cell migration and EMT through SMURF1 targeting [122]. SH3RF3 is an ubiquitin ligase involved in regulation of JNK pathway. There was miR-192-5p down regulation in PTC tissues and cell lines. MiR-192-5p reduced PTC cell migration and EMT, while increased apoptosis by SH3RF3 targeting [123].

Conclusions

Despite recent progresses in TC diagnosis and treatment, there is still a high rate of tumor relapse and metastasis in these patients. Since, the early stage tumor detection can significantly reduce the tumor cell migration and relapse; it is necessary to suggest novel tumor markers for the early detection. MiRNAs as the critical regulators of tumor cell migration and progression, have higher stability in body fluids compared with mRNAs. Therefore, miRNAs can be suggested as non-invasive markers to predict the tumor relapse in TC patients. MiRNA-based treatment can be performed by targeting the deregulated miRNAs via anti-miRNA oligonucleotides and molecular sponges. However, the side effects can be observed because of the negative impact of anti-miRs on normal physiological functions. Therefore, site-specific delivery of anti-miRs by the effective methods is an important issue to reduce optimal concentration and side effects. Vectors and nano-carriers are the main delivery methods for the anti-miRs that can be effective in combination with chemotherapy drugs in TC treatment.

Taking miRNAs from bench to clinic requires safe delivery methods, restriction of off-target effects, and reduced toxicity and immune responses. The development of miRNA based treatments consists of the preclinical studies and clinical trials. Expression analysis of specific miRNA is quantified through PCR-based methods. MiRNAs are validated via reporter gene assays vectors, miRNA mimics, or inhibitors. Design of therapeutic miRNAs requires regulating the expression of candidate miRNAs through stabilization and encapsulation into nano-carriers and characterization for specific targeting. In vitro studies are also required to evaluate the selectivity, affinity, toxicity, dose-response, and the effects of miRNA-loaded nano-carriers on multiple biological processes in cell lines. Animal studies for candidate therapeutic miRNAs are also needed to evaluate the toxicity and biosafety, animal behavior, and pharmacokinetics. The clinical trial studies require a powerful evaluation of single and multiple doses, side effects, and long-term follow-ups in pre-clinical studies.

In present review, we have summarized all of the miRNAs that have been involved in thyroid tumor cells migration and invasion to pave the way of introducing a non-invasive diagnostic and prognostic panel of miRNAs in TC. We categorized the reported miRNAs based on their involved molecular processes to clarify their roles during thyroid tumor cells migration. It was observed that the miRNAs mainly exert their roles in thyroid tumor cell migration and invasion through regulation of PI3K/AKT and WNT signaling pathways. However, whether miRNA based treatment can be effective in suppression of TC tumor relapse and migration, needs further animal studies to approve the long-term safety of delivery tools in clinical practice. Moreover, the majority of clinical studies about the role of miRNAs in thyroid tumor cell migration have been based on the expressional analysis in tumor tissues. Indeed, it is also necessary to evaluate the circulating levels of miRNAs in TC patients to suggest them as non-invasive diagnostic markers.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

TC:

Thyroid cancer

WDTC:

Well-differentiated TC

PDTC:

Poorly-differentiated TC

ATC:

Anaplastic thyroid carcinomas

PTC:

Papillary thyroid carcinoma

FTC:

Follicular thyroid carcinoma

MI-FTC:

Minimally invasive FTC

WI-FTC:

Widely invasive FTC

EMT:

Epithelial-to-mesenchymal transition

E-CAD:

E-cadherin

PI3K:

Phosphatidylinositol-3-kinase

FOXN3:

Forkhead Box N3

YAP1:

Yes-associated protein 1

ceRNA:

Competitively endogenous RNA

JAK:

Janus kinases

ROCK:

Rho-associated kinase family

SPHKs:

Sphingosine kinases

PKC-θ:

Protein kinase C-theta

PAK1:

P21-activated kinase

HMGA2:

High- mobility group-A2 gene

ncRNAs:

Non-coding RNAs

lncRNAs:

Long non-coding RNAs

miRNAs:

MicroRNAs

circRNAs:

Circular RNAs

YY1:

Yin Yang 1

PcG:

Polycomb-group

BCL-2:

B-cell lymphoma 2

RCA:

Rolling circle amplification

SDA:

Strand displacement amplification

LAMP:

Loop-mediated isothermal amplification

TAGLN2:

Transgelin-2

GPX4:

Glutathione peroxidase 4

References

  1. Goodarzi E, et al. Epidemiology, incidence and mortality of thyroid cancer and their relationship with the human development index in the world: an ecology study in 2018. Adv Hum Biology. 2019;9(2):162.

    Article  Google Scholar 

  2. Maha R, et al. Association of polymorphisms in estrogen and thyroid hormone receptors with thyroid cancer risk. J Recept Signal Transduction. 2009;29(2):113–8.

    Article  CAS  Google Scholar 

  3. Liu Y, et al. Bioinformatics analysis to screen key genes in papillary thyroid carcinoma. Oncol Lett. 2020;19(1):195–204.

    PubMed  Google Scholar 

  4. Wu J, et al. Expression of EMT regulators TWIST, SLUG, and SNAIL in follicular thyroid tumours may relate to widely invasive, poorly differentiated, and distant metastasis. Histopathology. 2019;74(5):780–91.

    Article  PubMed  Google Scholar 

  5. Sharifi A, et al. Predictors of regional lymph node recurrence after initial thyroidectomy in patients with thyroid cancer. J thyroid res. 2016;2016:4127278.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jukkola A, et al. Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications. Endocrine-related Cancer. 2004;11(3):571–9.

    Article  PubMed  Google Scholar 

  7. Holler T, et al. Prognostic factors in patients with multiple recurrences of well-differentiated thyroid carcinoma. J Oncol. 2009;2009:650340.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Liu Y, Su L, Xiao H. Review of factors related to the thyroid cancer epidemic. Int j endocrinol. 2017;2017:5308635.

    Article  PubMed  PubMed Central  Google Scholar 

  9. La Vecchia C, et al. Thyroid cancer mortality and incidence: a global overview. Int J Cancer. 2015;136(9):2187–95.

    Article  PubMed  CAS  Google Scholar 

  10. Lehrer S, Rosenzweig KE. Cold climate is a risk factor for thyroid cancer. Clin Thyroidol. 2014;26(10):273–6.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. cancer j clin. 2018; 68(6):394–424.

    Article  Google Scholar 

  12. Lan L, et al. Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells. Int J Oncol. 2013;43(1):113–20.

    Article  CAS  PubMed  Google Scholar 

  13. Chen L, et al. Arenobufagin inhibits prostate cancer epithelial-mesenchymal transition and metastasis by down-regulating β-catenin. Pharmacol Res. 2017;123:130–42.

    Article  CAS  PubMed  Google Scholar 

  14. Shakib H, Rajabi S, Dehghan MH, Mashayekhi FJ, Safari-Alighiarloo N, Hedayati M. Epithelial-to-mesenchymal transition in thyroid cancer: a comprehensive review. Endocrine. 2019;66(3):435-55.

  15. Liu Y, et al. microRNA-510-5p promotes thyroid cancer cell proliferation, migration, and invasion through suppressing SNHG15. J Cell Biochem. 2019;120:11738.

    Article  CAS  Google Scholar 

  16. Mikami S, et al. Expression of Snail and Slug in renal cell carcinoma: E-cadherin repressor Snail is associated with cancer invasion and prognosis. Lab Invest. 2011;91(10):1443–58.

    Article  CAS  PubMed  Google Scholar 

  17. Oliveto S, et al. Role of microRNAs in translation regulation and cancer. World J Biol Chem. 2017;8(1):45.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sánchez-Tilló E, et al. EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cell Mol Life Sci. 2012;69(20):3429–56.

    Article  PubMed  CAS  Google Scholar 

  20. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110.

    Article  PubMed  CAS  Google Scholar 

  21. Forghanifard MM, et al. TWIST1 upregulates the MAGEA4 oncogene. Mol Carcinog. 2017;56(3):877–85.

    Article  CAS  PubMed  Google Scholar 

  22. Tang H, et al. AKT-ions with a TWIST between EMT and MET. Oncotarget. 2016;7(38):62767–77.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Moghbeli M, et al. Role of MAML1 in targeted therapy against the esophageal cancer stem cells. J Transl Med. 2019;17(1):126.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Leong KG, et al. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med. 2007;204(12):2935–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Díaz-López A, Moreno-Bueno G, Cano A. Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives. Cancer Manage Res. 2014;6:205.

    Google Scholar 

  26. Fuziwara CS, Kimura ET. MicroRNA deregulation in anaplastic thyroid cancer biology. Int j endocrinol. 2014;2014:743450.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Stokowy T, Gawel D, Wojtas B. Differences in miRNA and mRNA profile of papillary thyroid cancer variants. Int j endocrinol. 2016;2016:1427042.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Celano M, et al. MicroRNAs as biomarkers in thyroid carcinoma. Int j genom. 2017;2017:6496570.

    Google Scholar 

  29. Price C, Chen J. MicroRNAs in cancer biology and therapy: current status and perspectives. Genes & diseases. 2014;1(1):53–63.

    Article  Google Scholar 

  30. Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med. 2012;4(3):143–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Boufraqech M, Klubo-Gwiezdzinska J, Kebebew E. MicroRNAs in the thyroid. Best Pract Res Clin Endocrinol Metab. 2016;30(5):603–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhu G, Xie L, Miller D. Expression of MicroRNAs in thyroid carcinoma. In: Bioinformatics in MicroRNA Research. Springer; 2017. p. 261–80.

  33. Siddika T, Heinemann IU. Bringing MicroRNAs to light: methods for MicroRNA quantification and visualization in live cells. Front Bioeng Biotechnol. 2021;8:1534.

    Article  Google Scholar 

  34. Cui M, et al. Circulating microRNAs in cancer: potential and challenge. Front Genet. 2019;10:626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu J, et al. Next generation sequencing for profiling expression of miRNAs: technical progress and applications in drug development. J Biomed Sci Eng. 2011;4(10):666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Miska EA, et al. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol. 2004;5(9):1–13.

    Article  Google Scholar 

  37. Xu H, et al. DNA nanostructures from palindromic rolling circle amplification for the fluorescent detection of cancer-related microRNAs. Talanta. 2019;192:175–81.

    Article  CAS  PubMed  Google Scholar 

  38. Chen M, Zhao H. Next-generation sequencing in liquid biopsy: cancer screening and early detection. Hum Genomics. 2019;13(1):1–10.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Preethi KA, et al. Liquid biopsy: Exosomal microRNAs as novel diagnostic and prognostic biomarkers in cancer. Mol Cancer. 2022;21(1):1–15.

    Article  CAS  Google Scholar 

  40. Shigeyasu K, et al. Emerging role of microRNAs as liquid biopsy biomarkers in gastrointestinal cancers. Clin Cancer Res. 2017;23(10):2391–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhuang J, et al. MicroRNA–497 inhibits cellular proliferation, migration and invasion of papillary thyroid cancer by directly targeting AKT3. Mol Med Rep. 2017;16(5):5815–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Boufraqech M, et al. miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. Endocr Relat Cancer. 2014;21(4):517–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lin Y, et al. miR-217 inhibits proliferation, migration, and invasion via targeting AKT3 in thyroid cancer. Biomed Pharmacother. 2017;95:1718–24.

    Article  CAS  PubMed  Google Scholar 

  44. You A, et al. MicroRNA-203 restrains epithelial–mesenchymal transition, invasion and migration of papillary thyroid cancer by downregulating AKT3. Cell Cycle. 2020;19(10):1105–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sui GQ, et al. MicroRNA-338-3p inhibits thyroid cancer progression through targeting AKT3. Am J Cancer Res. 2017;7(5):1177–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Li R, et al. miR-29a suppresses growth and metastasis in papillary thyroid carcinoma by targeting AKT3. Tumour Biol. 2016;37(3):3987–96.

    Article  CAS  PubMed  Google Scholar 

  47. Zhou B, et al. Let-7a inhibits migration, invasion and tumor growth by targeting AKT2 in papillary thyroid carcinoma. Oncotarget. 2017;8(41):69746–55.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wang X, Qi M. miR-718 is involved in malignancy of papillary thyroid cancer through repression of PDPK1. Pathol Res Pract. 2018;214(11):1787–93.

    Article  CAS  PubMed  Google Scholar 

  49. Bu Q, et al. MiR-125b inhibits anaplastic thyroid cancer cell migration and invasion by targeting PIK3CD. Biomed Pharmacother. 2017;88:443–8.

    Article  CAS  PubMed  Google Scholar 

  50. Liu J, et al. MicroRNA-363-3p inhibits papillary thyroid carcinoma progression by targeting PIK3CA. Am J Cancer Res. 2017;7(1):148–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yin Y, et al. LINC01087 Promotes the Proliferation, Migration, and Invasion of Thyroid Cancer Cells by Upregulating PPM1E. J Oncol. 2022;2022:7787378.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Zhang D, et al. CircRNA circTIAM1 promotes papillary thyroid cancer progression through the miR-646/HNRNPA1 signaling pathway. Cell Death Discov. 2022;8(1):21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang Y, et al. miR-30b-5p inhibits proliferation, invasion, and migration of papillary thyroid cancer by targeting GALNT7 via the EGFR/PI3K/AKT pathway. Cancer Cell Int. 2021;21(1):618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dong S, et al. microRNA-141 inhibits thyroid cancer cell growth and metastasis by targeting insulin receptor substrate 2. Am J Transl Res. 2016;8(3):1471–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhao J, et al. MicroRNA–766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway. Int J Oncol. 2019;54(1):315–25.

    CAS  PubMed  Google Scholar 

  56. Han J, et al. miR-215 suppresses papillary thyroid cancer proliferation, migration, and invasion through the AKT/GSK-3β/Snail signaling by targeting ARFGEF1. Cell Death Dis. 2019;10(3):195.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Minna E, et al. miR-451a is underexpressed and targets AKT/mTOR pathway in papillary thyroid carcinoma. Oncotarget. 2016;7(11):12731–47.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ramírez-Moya J, Wert-Lamas L, Santisteban P. MicroRNA-146b promotes PI3K/AKT pathway hyperactivation and thyroid cancer progression by targeting PTEN. Oncogene. 2018;37(25):3369–83.

    Article  PubMed  CAS  Google Scholar 

  59. Wang WJ, et al. miR-671-5p repressed progression of papillary thyroid carcinoma via TRIM14. Kaohsiung J Med Sci. 2021;37(11):983–90.

    Article  CAS  PubMed  Google Scholar 

  60. Wang W, et al. Circular RNA circWDR27 Promotes Papillary Thyroid Cancer Progression by Regulating miR-215-5p/TRIM44 Axis. Onco Targets Ther. 2021;14:3281–93.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Li YQ, et al. LINC00958/miR-627 signal axis regulates the proliferation, migration, and invasion of thyroid papillary carcinoma cells by TRIM44. Kaohsiung J Med Sci. 2022;38(5):415–24.

    Article  CAS  PubMed  Google Scholar 

  62. Yu S, et al. miR-3619-3p promotes papillary thyroid carcinoma progression via Wnt/β-catenin pathway. Ann Transl Med. 2019;7(22):643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wen Q, et al. miR-126 inhibits papillary thyroid carcinoma growth by targeting LRP6. Oncol Rep. 2015;34(4):2202–10.

    Article  CAS  PubMed  Google Scholar 

  64. Kong W, et al. MiR-381-3p inhibits proliferation, migration and invasion by targeting LRP6 in papillary thyroid carcinoma. Eur Rev Med Pharmacol Sci. 2018;22(12):3804–11.

    CAS  PubMed  Google Scholar 

  65. Shi D, et al. MicroRNA-26a-5p inhibits proliferation, invasion and metastasis by repressing the expression of Wnt5a in papillary thyroid carcinoma. Onco Targets Ther. 2019;12:6605–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wu L, et al. miR-329 inhibits papillary thyroid cancer progression via direct targeting WNT1. Oncol Lett. 2018;16(3):3561–8.

    PubMed  PubMed Central  Google Scholar 

  67. Zhang ZJ, Xiao Q, Li XY. MicroRNA-574-5p directly targets FOXN3 to mediate thyroid cancer progression via Wnt/β-catenin signaling pathway. Pathol Res Pract. 2020;216(6):152939.

    Article  CAS  PubMed  Google Scholar 

  68. Yi T, et al. MicroRNA-1270 modulates papillary thyroid cancer cell development by regulating SCAI. Biomed Pharmacother. 2019;109:2357–64.

    Article  CAS  PubMed  Google Scholar 

  69. Fang L, Kong D, Xu W. MicroRNA-625-3p promotes the proliferation, migration and invasion of thyroid cancer cells by up-regulating astrocyte elevated gene 1. Biomed Pharmacother. 2018;102:203–11.

    Article  CAS  PubMed  Google Scholar 

  70. Song Z, et al. microRNA-564 inhibits the aggressive phenotypes of papillary thyroid cancer by directly targeting astrocyte-elevated gene-1. Onco Targets Ther. 2019;12:4869–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Li D, et al. miR–205 targets YAP1 and inhibits proliferation and invasion in thyroid cancer cells. Mol Med Rep. 2018;18(2):1674–81.

    CAS  PubMed  Google Scholar 

  72. Zhao H, et al. LINC01816 promotes the migration, invasion and epithelialmesenchymal transition of thyroid carcinoma cells by sponging miR34c5p and regulating CRABP2 expression levels. Oncol Rep. 2021;45(5):81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang Z, et al. MicroRNA-663 suppresses cell invasion and migration by targeting transforming growth factor beta 1 in papillary thyroid carcinoma. Tumour Biol. 2016;37(6):7633–44.

    Article  CAS  PubMed  Google Scholar 

  74. Lima CR, et al. MiRNA-146b-5p upregulates migration and invasion of different Papillary Thyroid Carcinoma cells. BMC Cancer. 2016;16:108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Zhang X, et al. MicroRNA 483-3p targets Pard3 to potentiate TGF-β1-induced cell migration, invasion, and epithelial–mesenchymal transition in anaplastic thyroid cancer cells. Oncogene. 2019;38(5):699–715.

    Article  PubMed  CAS  Google Scholar 

  76. Zhang W, Ji W, Zhao X. MiR-155 promotes anaplastic thyroid cancer progression by directly targeting SOCS1. BMC Cancer. 2019;19(1):1093.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Mei Z, et al. Interleukin-23 Facilitates Thyroid Cancer Cell Migration and Invasion by Inhibiting SOCS4 Expression via MicroRNA-25. PLoS ONE. 2015;10(10):e0139456.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Qian Y, et al. MicroRNA–126 is downregulated in thyroid cancer cells, and regulates proliferation, migration and invasion by targeting CXCR4. Mol Med Rep. 2016;14(1):453–9.

    Article  CAS  PubMed  Google Scholar 

  79. Liu Y, et al. Long non-coding RNA DUXAP8 promotes the cell proliferation, migration, and invasion of papillary thyroid carcinoma via miR-223-3p mediated regulation of CXCR4. Bioengineered. 2021;12(1):496–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Dong S, et al. MiR-137 acts as a tumor suppressor in papillary thyroid carcinoma by targeting CXCL12. Oncol Rep. 2016;35(4):2151–8.

    Article  CAS  PubMed  Google Scholar 

  81. Zheng X, et al. circPVT1 regulates medullary thyroid cancer growth and metastasis by targeting miR-455-5p to activate CXCL12/CXCR4 signaling. J Exp Clin Cancer Res. 2021;40(1):157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Leone V, et al. MiR-1 is a tumor suppressor in thyroid carcinogenesis targeting CCND2, CXCR4, and SDF-1alpha. J Clin Endocrinol Metab. 2011;96(9):E1388-98.

    Article  PubMed  CAS  Google Scholar 

  83. Wang Z, et al. miR-873-5p Inhibits Cell Migration and Invasion of Papillary Thyroid Cancer via Regulation of CXCL16. Onco Targets Ther. 2020;13:1037–46.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Wang P, et al. MicroRNA-497 inhibits thyroid cancer tumor growth and invasion by suppressing BDNF. Oncotarget. 2017;8(2):2825–34.

    Article  PubMed  Google Scholar 

  85. Zheng H, et al. Circ_0079558 promotes papillary thyroid cancer progression by binding to miR-26b-5p to activate MET/AKT signaling. Endocr J. 2021;68(11):1247–66.

    Article  CAS  PubMed  Google Scholar 

  86. Wang XZ, et al. Over-expression of microRNA-375 inhibits papillary thyroid carcinoma cell proliferation and induces cell apoptosis by targeting ERBB2. J Pharmacol Sci. 2016;130(2):78–84.

    Article  CAS  PubMed  Google Scholar 

  87. Zeng L, et al. Circular RNA Pvt1 oncogene (CircPVT1) promotes the progression of papillary thyroid carcinoma by activating the Wnt/beta-catenin signaling pathway and modulating the ratio of microRNA-195 (miR-195) to vascular endothelial growth factor A (VEGFA) expression. Bioengineered. 2021;12(2):11795–810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bi CL, et al. MicroRNA-520a-3p suppresses epithelial-mesenchymal transition, invasion, and migration of papillary thyroid carcinoma cells via the JAK1-mediated JAK/STAT signaling pathway. J Cell Physiol. 2019;234(4):4054–67.

    Article  CAS  PubMed  Google Scholar 

  89. Li R, et al. MicroRNA-361-5p inhibits papillary thyroid carcinoma progression by targeting ROCK1. Biomed Pharmacother. 2018;102:988–95.

    Article  CAS  PubMed  Google Scholar 

  90. Cheng L, et al. MicroRNA-150 targets Rho-associated protein kinase 1 to inhibit cell proliferation, migration and invasion in papillary thyroid carcinoma. Mol Med Rep. 2017;16(2):2217–24.

    Article  CAS  PubMed  Google Scholar 

  91. Cao XZ, Bin H, Zang ZN. MiR-128 suppresses the growth of thyroid carcinoma by negatively regulating SPHK1. Biomed Pharmacother. 2019;109:1960–6.

    Article  CAS  PubMed  Google Scholar 

  92. Xue KC, et al. MiR-577 inhibits papillary thyroid carcinoma cell proliferation, migration and invasion by targeting SphK2. Eur Rev Med Pharmacol Sci. 2017;21(17):3794–800.

    PubMed  Google Scholar 

  93. Qiu W, et al. MicroRNA-613 inhibits cell growth, migration and invasion of papillary thyroid carcinoma by regulating SphK2. Oncotarget. 2016;7(26):39907–15.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Gu L, Sun W. MiR-539 inhibits thyroid cancer cell migration and invasion by directly targeting CARMA1. Biochem Biophys Res Commun. 2015;464(4):1128–33.

    Article  CAS  PubMed  Google Scholar 

  95. Wang J, Xiao T, Zhao M. MicroRNA-675 directly targets MAPK1 to suppress the oncogenicity of papillary thyroid cancer and is sponged by long non-coding RNA RMRP. Onco Targets Ther. 2019;12:7307–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yue K, et al. microRNA-7 regulates cell growth, migration and invasion via direct targeting of PAK1 in thyroid cancer. Mol Med Rep. 2016;14(3):2127–34.

    Article  CAS  PubMed  Google Scholar 

  97. Wang C, et al. Hsa-microRNA-101 suppresses migration and invasion by targeting Rac1 in thyroid cancer cells. Oncol Lett. 2014;8(4):1815–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Li H, et al. Roles of microRNA let-7b in papillary thyroid carcinoma by regulating HMGA2. Tumour Biol. 2017;39(10):1010428317719274.

    Article  PubMed  Google Scholar 

  99. Ding C, et al. MiR-let-7e inhibits invasion and magration and regulates HMGB1 expression in papillary thyroid carcinoma. Biomed Pharmacother. 2019;110:528–36.

    Article  CAS  PubMed  Google Scholar 

  100. Li D, et al. Function of miR-212 as a tumor suppressor in thyroid cancer by targeting SIRT1. Oncol Rep. 2018;39(2):695–702.

    Article  CAS  PubMed  Google Scholar 

  101. Guan H, et al. Down-regulation of miR-144 promotes thyroid cancer cell invasion by targeting ZEB1 and ZEB2. Endocrine. 2015;48(2):566–74.

    Article  CAS  PubMed  Google Scholar 

  102. Wu G, et al. miR-429 suppresses cell growth and induces apoptosis of human thyroid cancer cell by targeting ZEB1. Artif Cells Nanomed Biotechnol. 2019;47(1):548–54.

    Article  CAS  PubMed  Google Scholar 

  103. Kan Q, Su Y, Yang H. MicroRNA-335 is downregulated in papillary thyroid cancer and suppresses cancer cell growth, migration and invasion by directly targeting ZEB2. Oncol Lett. 2017;14(6):7622–8.

    PubMed  PubMed Central  Google Scholar 

  104. Xiang Y, et al. Circular RNA VANGL1 Facilitates Migration and Invasion of Papillary Thyroid Cancer by Modulating the miR-194/ZEB1/EMT Axis. J Oncol. 2022;2022:4818651.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Guo H, Zhang L. MicroRNA-30a suppresses papillary thyroid cancer cell proliferation, migration and invasion by directly targeting E2F7. Exp Ther Med. 2019;18(1):209–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang F, Li Z, Sun B. miR-544 inhibits the migration and invasion of anaplastic thyroid cancer by targeting Yin Yang-1. Oncol Lett. 2019;17(3):2983–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Wang L, et al. Overexpression miR-211-5p hinders the proliferation, migration, and invasion of thyroid tumor cells by downregulating SOX11. J Clin Lab Anal. 2018;32(3):e22293.

    Article  CAS  Google Scholar 

  108. Wen X, Du J, Wang X. Circ_0039411 promotes papillary thyroid carcinoma development through mediating the miR-423-5p/SOX4 signaling. Int J Biol Markers. 2021;36(4):10–20.

    Article  CAS  PubMed  Google Scholar 

  109. Esposito F, et al. Down-regulation of the miR-25 and miR-30d contributes to the development of anaplastic thyroid carcinoma targeting the polycomb protein EZH2. J Clin Endocrinol Metab. 2012;97(5):E710-8.

    Article  PubMed  CAS  Google Scholar 

  110. Liu H, et al. MicroRNA-524-5p suppresses the progression of papillary thyroid carcinoma cells via targeting on FOXE1 and ITGA3 in cell autophagy and cycling pathways. J Cell Physiol. 2019;234(10):18382–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang WL, et al. miR-206 inhibits metastasis-relevant traits by degrading MRTF-A in anaplastic thyroid cancer. Int J Oncol. 2015;47(1):133–42.

    Article  CAS  PubMed  Google Scholar 

  112. Jiang YM, et al. CircLDLR Promotes Papillary Thyroid Carcinoma Tumorigenicity by Regulating miR-637/LMO4 Axis. Dis Markers. 2021;2021:3977189.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Wang P, et al. miR-206 inhibits thyroid cancer proliferation and invasion by targeting RAP1B. J Cell Biochem. 2019;120(11):18927–36.

    Article  CAS  PubMed  Google Scholar 

  114. Xiong Y, et al. miR-126-3p Inhibits Thyroid Cancer Cell Growth and Metastasis, and Is Associated with Aggressive Thyroid Cancer. PLoS ONE. 2015;10(8):e0130496.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Boufraqech M, et al. miR30a inhibits LOX expression and anaplastic thyroid cancer progression. Cancer Res. 2015;75(2):367–77.

    Article  CAS  PubMed  Google Scholar 

  116. Huang Y, et al. MiR-613 inhibits the proliferation, migration, and invasion of papillary thyroid carcinoma cells by directly targeting TAGLN2. Cancer Cell Int. 2021;21(1):494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Chen W, et al. Circular RNA circKIF4A facilitates the malignant progression and suppresses ferroptosis by sponging miR-1231 and upregulating GPX4 in papillary thyroid cancer. Aging. 2021;13(12):16500–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Cheng Q, et al. MiR-618 inhibits anaplastic thyroid cancer by repressing XIAP in one ATC cell line. Ann Endocrinol (Paris). 2014;75(4):187–93.

    Article  Google Scholar 

  119. Lu Z, et al. MicroRNA-15 regulates the proliferation, migration and invasion of thyroid cancer cells by targeting Bcl-2. J buon. 2019;24(5):2114–9.

    PubMed  Google Scholar 

  120. Sun W, Yin D. Long noncoding RNA CASC7 inhibits the proliferation and migration of papillary thyroid cancer cells by inhibiting miR-34a-5p. J Physiol Sci. 2021;71(1):9.

    Article  CAS  PubMed  Google Scholar 

  121. Liu F, et al. miR-214 regulates papillary thyroid carcinoma cell proliferation and metastasis by targeting PSMD10. Int J Mol Med. 2018;42(6):3027–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Bian S. miR-4319 inhibited the development of thyroid cancer by modulating FUS-stabilized SMURF1. J Cell Biochem. 2020;121(1):174–82.

    Article  CAS  PubMed  Google Scholar 

  123. Fu S, et al. MiR-192-5p inhibits proliferation, migration, and invasion in papillary thyroid carcinoma cells by regulation of SH3RF3. Biosci Rep. 2021;41(9):BSR20210342.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Cain RJ, Ridley AJ. Phosphoinositide 3-kinases in cell migration. Biol Cell. 2009;101(1):13–29.

    Article  CAS  PubMed  Google Scholar 

  125. Xia P, Xu XY. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res. 2015;5(5):1602–9.

    PubMed  PubMed Central  Google Scholar 

  126. Petrulea MS, et al. PI3K/Akt/mTOR: A promising therapeutic target for non-medullary thyroid carcinoma. Cancer Treat Rev. 2015;41(8):707–13.

    Article  CAS  PubMed  Google Scholar 

  127. Agarwal E, Brattain MG, Chowdhury S. Cell survival and metastasis regulation by Akt signaling in colorectal cancer. Cell Signal. 2013;25(8):1711–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kang B, et al. Evaluation of hepatic-metastasis risk of colorectal cancer upon the protein signature of PI3K/AKT pathway. J Proteome Res. 2008;7(8):3507–15.

    Article  CAS  PubMed  Google Scholar 

  129. Akao Y, Nakagawa Y, Naoe T. let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. Biol Pharm Bull. 2006;29(5):903–6.

    Article  CAS  PubMed  Google Scholar 

  130. Volinia S, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Nat Acad Sci. 2006;103(7):2257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yang X, et al. Up-regulation of microRNA-203 inhibits myocardial fibrosis and oxidative stress in mice with diabetic cardiomyopathy through the inhibition of PI3K/Akt signaling pathway via PIK3CA. Gene. 2019;715:143995.

    Article  CAS  PubMed  Google Scholar 

  132. Whiteman EL, Cho H, Birnbaum MJ. Role of Akt/protein kinase B in metabolism. Trends Endocrinol Metab. 2002;13(10):444–51.

    Article  CAS  PubMed  Google Scholar 

  133. Mora A, et al. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004;15(2):161–70.

    Article  CAS  PubMed  Google Scholar 

  134. Chen MB, et al. AMPKalpha phosphatase Ppm1E upregulation in human gastric cancer is required for cell proliferation. Oncotarget. 2017;8(19):31288–96.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Roy R, et al. hnRNPA1 couples nuclear export and translation of specific mRNAs downstream of FGF-2/S6K2 signalling. Nucleic Acids Res. 2014;42(20):12483–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Chen X, et al. miR-141 is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression. Clin Cancer Res. 2014;20(10):2617–30.

    Article  CAS  PubMed  Google Scholar 

  137. Zhou X, et al. MiR-141 Inhibits Gastric Cancer Proliferation by Interacting with Long Noncoding RNA MEG3 and Down-Regulating E2F3 Expression. Dig Dis Sci. 2015;60(11):3271–82.

    Article  CAS  PubMed  Google Scholar 

  138. Wu SM, et al. MiR-141 targets ZEB2 to suppress HCC progression. Tumour Biol. 2014;35(10):9993–7.

    Article  CAS  PubMed  Google Scholar 

  139. Liu Y, et al. MiR-141 suppresses the migration and invasion of HCC cells by targeting Tiam1. PLoS ONE. 2014;9(2):e88393.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. van Jaarsveld MT, et al. miR-141 regulates KEAP1 and modulates cisplatin sensitivity in ovarian cancer cells. Oncogene. 2013;32(36):4284–93.

    Article  PubMed  CAS  Google Scholar 

  141. Jia Y, et al. Inhibition of SOX17 by microRNA 141 and methylation activates the WNT signaling pathway in esophageal cancer. J Mol Diagn. 2012;14(6):577–85.

    Article  CAS  PubMed  Google Scholar 

  142. Tsuji Y, et al. Subcellular localization of insulin receptor substrate family proteins associated with phosphatidylinositol 3-kinase activity and alterations in lipolysis in primary mouse adipocytes from IRS-1 null mice. Diabetes. 2001;50(6):1455–63.

    Article  CAS  PubMed  Google Scholar 

  143. Sesti G, et al. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. Faseb j. 2001;15(12):2099–111.

    Article  CAS  PubMed  Google Scholar 

  144. Zhang P, et al. MiR-338-3p inhibits the growth and invasion of non-small cell lung cancer cells by targeting IRS2. Am J Cancer Res. 2017;7(1):53–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. de M Campos P, et al. IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in JAK2V617F-positive myeloproliferative neoplasms. Oncotarget. 2016;7(6):6948–59.

  146. Liu H, et al. The upregulation of miRNA-146a inhibited biological behaviors of ESCC through inhibition of IRS2. Tumor Biology. 2016;37(4):4641–7.

    Article  CAS  PubMed  Google Scholar 

  147. Pollard PJ, Wortham NC, Tomlinson IP. The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase. Ann Med. 2003;35(8):632–9.

    Article  CAS  PubMed  Google Scholar 

  148. Miettinen M, Lasota J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int J Biochem Cell Biol. 2014;53:514–9.

    Article  CAS  PubMed  Google Scholar 

  149. Iwashita H, et al. Succinate dehydrogenase B-deficient renal cell carcinoma: A case report with novel germline mutation. Pathol Int. 2017;67(11):585–9.

    Article  CAS  PubMed  Google Scholar 

  150. Letouzé E, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013;23(6):739–52.

    Article  PubMed  CAS  Google Scholar 

  151. Fuhrmann DC, Wittig I, Brüne B. TMEM126B deficiency reduces mitochondrial SDH oxidation by LPS, attenuating HIF-1α stabilization and IL-1β expression. Redox Biol. 2019;20:204–16.

    Article  CAS  PubMed  Google Scholar 

  152. Chen L, et al. Succinate dehydrogenase subunit B inhibits the AMPK-HIF-1α pathway in human ovarian cancer in vitro. J Ovarian Res. 2014;7:115.

    PubMed  PubMed Central  Google Scholar 

  153. King A, Selak MA, Gottlieb E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene. 2006;25(34):4675–82.

    Article  CAS  PubMed  Google Scholar 

  154. Wang H, Chen Y, Wu G. SDHB deficiency promotes TGFβ-mediated invasion and metastasis of colorectal cancer through transcriptional repression complex SNAIL1-SMAD3/4. Transl Oncol. 2016;9(6):512–20.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Zhao X, Li Y, Zhou Y. MicroRNA-96-3p promotes metastasis of papillary thyroid cancer through targeting SDHB. Cancer Cell Int. 2019;19(1):287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Lue H, et al. Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity. Oncogene. 2007;26(35):5046–59.

    Article  CAS  PubMed  Google Scholar 

  157. Pallante P, et al. Deregulation of microRNA expression in thyroid neoplasias. Nat Rev Endocrinol. 2014;10(2):88–101.

    Article  CAS  PubMed  Google Scholar 

  158. Deng X, et al. MiR-146b-5p promotes metastasis and induces epithelial-mesenchymal transition in thyroid cancer by targeting ZNRF3. Cell Physiol Biochem. 2015;35(1):71–82.

    Article  CAS  PubMed  Google Scholar 

  159. Chen J, et al. TRIM14 regulates melanoma malignancy via PTEN/PI3K/AKT and STAT3 pathways. Aging. 2021;13(9):13225–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Abbaszadegan MR, et al. WNT and NOTCH signaling pathways as activators for epidermal growth factor receptor in esophageal squamous cell carcinoma. Cell Mol Biol Lett. 2018;23:42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Moghbeli M, et al. Correlation of Wnt and NOTCH pathways in esophageal squamous cell carcinoma. J Cell Commun Signal. 2016;10(2):129–35.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Moghbeli M, et al. Correlation Between Meis1 and Msi1 in Esophageal Squamous Cell Carcinoma. J Gastrointest Cancer. 2016;47(3):273–7.

    Article  CAS  PubMed  Google Scholar 

  163. Sastre-Perona A, Santisteban P. Role of the wnt pathway in thyroid cancer. Front Endocrinol (Lausanne). 2012;3:31.

    Article  CAS  Google Scholar 

  164. Peröbner I, et al. LRP6 mediates Wnt/β-catenin signaling and regulates adipogenic differentiation in human mesenchymal stem cells. Int J Biochem Cell Biol. 2012;44(11):1970–82.

    Article  PubMed  CAS  Google Scholar 

  165. Brown SD, et al. Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family. Biochem Biophys Res Commun. 1998;248(3):879–88.

    Article  CAS  PubMed  Google Scholar 

  166. Wang L, et al. Expression of hepatic Wnt5a and its clinicopathological features in patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2018;17(3):227–32.

    Article  PubMed  Google Scholar 

  167. Dai Y, et al. Loss of FOXN3 in colon cancer activates beta-catenin/TCF signaling and promotes the growth and migration of cancer cells. Oncotarget. 2017;8(6):9783–93.

    Article  PubMed  Google Scholar 

  168. Brandt DT, et al. SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of beta1-integrin. Nat Cell Biol. 2009;11(5):557–68.

    Article  CAS  PubMed  Google Scholar 

  169. Chen X, et al. Downregulation of SCAI enhances glioma cell invasion and stem cell like phenotype by activating Wnt/beta-catenin signaling. Biochem Biophys Res Commun. 2014;448(2):206–11.

    Article  CAS  PubMed  Google Scholar 

  170. Kirschner MB, et al. Increased circulating miR-625-3p: a potential biomarker for patients with malignant pleural mesothelioma. J Thorac Oncol. 2012;7(7):1184–91.

    Article  CAS  PubMed  Google Scholar 

  171. Rasmussen MH, et al. miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells. Nat Commun. 2016;7:12436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Huang LL, et al. AEG-1 associates with metastasis in papillary thyroid cancer through upregulation of MMP2/9. Int J Oncol. 2017;51(3):812–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Bora-Singhal N, et al. YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate Self-Renewal and Vascular Mimicry of Stem-Like Cells. Stem Cells. 2015;33(6):1705–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Wu DM, et al. LncRNA SNHG15 acts as a ceRNA to regulate YAP1-Hippo signaling pathway by sponging miR-200a-3p in papillary thyroid carcinoma. Cell Death Dis. 2018;9(10):947.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Feng X, et al. CRABP2 regulates invasion and metastasis of breast cancer through hippo pathway dependent on ER status. J Exp Clin Cancer Res. 2019;38(1):361.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Al-Azayzih A, Gao F, Somanath PR. P21 activated kinase-1 mediates transforming growth factor β1-induced prostate cancer cell epithelial to mesenchymal transition. Biochim Biophys Acta. 2015;1853(5):1229–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Morrison CD, Parvani JG, Schiemann WP. The relevance of the TGF-β Paradox to EMT-MET programs. Cancer Lett. 2013;341(1):30–40.

    Article  CAS  PubMed  Google Scholar 

  178. Gudey SK, et al. TRAF6 stimulates the tumor-promoting effects of TGFβ type I receptor through polyubiquitination and activation of presenilin 1. Sci Signal. 2014;7(307):ra2.

    Article  PubMed  CAS  Google Scholar 

  179. Eloy C, et al. TGF-beta/Smad pathway and BRAF mutation play different roles in circumscribed and infiltrative papillary thyroid carcinoma. Virchows Arch. 2012;460(6):587–600.

    Article  CAS  PubMed  Google Scholar 

  180. Liu F, et al. TGF-β1 acts through miR-155 to down-regulate TP53INP1 in promoting epithelial-mesenchymal transition and cancer stem cell phenotypes. Cancer Lett. 2015;359(2):288–98.

    Article  PubMed  CAS  Google Scholar 

  181. Geraldo MV, Yamashita AS, Kimura ET. MicroRNA miR-146b-5p regulates signal transduction of TGF-β by repressing SMAD4 in thyroid cancer. Oncogene. 2012;31(15):1910–22.

    Article  CAS  PubMed  Google Scholar 

  182. Yu C, et al. MicroRNA-146b-3p Promotes Cell Metastasis by Directly Targeting NF2 in Human Papillary Thyroid Cancer. Thyroid. 2018;28(12):1627–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Suzuki A, Ohno S. The PAR-aPKC system: lessons in polarity. J Cell Sci. 2006;119(Pt 6):979–87.

    Article  CAS  PubMed  Google Scholar 

  184. Aranda V, Nolan ME, Muthuswamy SK. Par complex in cancer: a regulator of normal cell polarity joins the dark side. Oncogene. 2008;27(55):6878–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Duhen T, et al. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol. 2009;10(8):857–63.

    Article  CAS  PubMed  Google Scholar 

  186. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28(4):454–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Trifari S, et al. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol. 2009;10(8):864–71.

    Article  CAS  PubMed  Google Scholar 

  188. Wolk K, et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol. 2006;36(5):1309–23.

    Article  CAS  PubMed  Google Scholar 

  189. Boniface K, et al. A role for T cell-derived interleukin 22 in psoriatic skin inflammation. Clin Exp Immunol. 2007;150(3):407–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Zheng Y, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445(7128):648–51.

    Article  CAS  PubMed  Google Scholar 

  191. Jiang R, et al. IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer. 2013;13:59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Kim K, et al. Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation. Carcinogenesis. 2014;35(6):1352–61.

    Article  CAS  PubMed  Google Scholar 

  193. Zhang W, et al. Antiapoptotic activity of autocrine interleukin-22 and therapeutic effects of interleukin-22-small interfering RNA on human lung cancer xenografts. Clin Cancer Res. 2008;14(20):6432–9.

    Article  CAS  PubMed  Google Scholar 

  194. Jonatan D, et al. Sox17 regulates insulin secretion in the normal and pathologic mouse β cell. PLoS ONE. 2014;9(8):e104675.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Mei Z, et al. Interleukin-22 promotes papillary thyroid cancer cell migration and invasion through microRNA-595/Sox17 axis. Tumor Biology. 2016;37(9):11753–62.

    Article  CAS  PubMed  Google Scholar 

  196. Balkwill FR. The chemokine system and cancer. J Pathol. 2012;226(2):148–57.

    Article  CAS  PubMed  Google Scholar 

  197. Oh J, et al. Suppressors of cytokine signaling promote Fas-induced apoptosis through downregulation of NF-κB and mitochondrial Bfl-1 in leukemic T cells. J Immunol. 2012;189(12):5561–71.

    Article  CAS  PubMed  Google Scholar 

  198. Oppmann B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immun. 2000;13(5):715–25.

    Article  CAS  Google Scholar 

  199. Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(Suppl 4):S3–8.

    Article  CAS  PubMed  Google Scholar 

  200. Secchiero P, et al. Differential effects of stromal derived factor-1 alpha (SDF-1 alpha) on early and late stages of human megakaryocytic development. Anat Rec. 2000;260(2):141–7.

    Article  CAS  PubMed  Google Scholar 

  201. Nagasawa T. CXCL12/SDF-1 and CXCR4. Front Immunol. 2015;6:301.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Deng L, et al. CXCR6/CXCL16 functions as a regulator in metastasis and progression of cancer. Biochim Biophys Acta. 2010;1806:42–9.

    CAS  PubMed  Google Scholar 

  203. Sandhya VK, et al. A network map of BDNF/TRKB and BDNF/p75NTR signaling system. J Cell Commun Signal. 2013;7(4):301–7.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Muthuswamy SK, et al. ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat Cell Biol. 2001;3(9):785–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Basilico C, Moscatelli D. The FGF family of growth factors and oncogenes. Adv Cancer Res. 1992;59:115–65.

    Article  CAS  PubMed  Google Scholar 

  206. Yin Y, et al. MiR-195 Inhibits Tumor Growth and Metastasis in Papillary Thyroid Carcinoma Cell Lines by Targeting CCND1 and FGF2. Int J Endocrinol. 2017;2017:6180425.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. Riesco-Eizaguirre G, Santisteban P. New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy. Endocr Relat Cancer. 2007;14(4):957–77.

    Article  CAS  PubMed  Google Scholar 

  208. Patel KN, Shaha AR. Poorly differentiated and anaplastic thyroid cancer. Cancer Control. 2006;13(2):119–28.

    Article  PubMed  Google Scholar 

  209. Zhong WB, et al. Lovastatin suppresses invasiveness of anaplastic thyroid cancer cells by inhibiting Rho geranylgeranylation and RhoA/ROCK signaling. Endocr Relat Cancer. 2005;12(3):615–29.

    Article  CAS  PubMed  Google Scholar 

  210. Bergström JD, Westermark B, Heldin NE. Epidermal growth factor receptor signaling activates met in human anaplastic thyroid carcinoma cells. Exp Cell Res. 2000;259(1):293–9.

    Article  PubMed  CAS  Google Scholar 

  211. Kuan CT, Wikstrand CJ, Bigner DD. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer. 2001;8(2):83–96.

    Article  CAS  PubMed  Google Scholar 

  212. Larsen AK, et al. Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther. 2011;131(1):80–90.

    Article  CAS  PubMed  Google Scholar 

  213. Cascone T, et al. Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor-resistant human lung adenocarcinoma. J Clin Invest. 2011;121(4):1313–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Ferrer-Soler L, et al. An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: Gefitinib (Iressa) -induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review). Int J Mol Med. 2007;20(1):3–10.

    CAS  PubMed  Google Scholar 

  215. Zhang Z, et al. The miR-200 family regulates the epithelial-mesenchymal transition induced by EGF/EGFR in anaplastic thyroid cancer cells. Int J Mol Med. 2012;30(4):856–62.

    Article  CAS  PubMed  Google Scholar 

  216. Knipe RS, Tager AM, Liao JK. The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev. 2015;67(1):103–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Liu S. The ROCK signaling and breast cancer metastasis. Mol Biol Rep. 2011;38(2):1363–6.

    Article  CAS  PubMed  Google Scholar 

  218. Venkata JK, et al. Inhibition of sphingosine kinase 2 downregulates the expression of c-Myc and Mcl-1 and induces apoptosis in multiple myeloma. Blood. 2014;124(12):1915–25.

    Article  CAS  PubMed  Google Scholar 

  219. Shida D, et al. Targeting SphK1 as a new strategy against cancer. Curr Drug Targets. 2008;9(8):662–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Oskeritzian CA, et al. Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions. Blood. 2008;111(8):4193–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Liu H, et al. Sphingosine kinases: a novel family of lipid kinases. Prog Nucleic Acid Res Mol Biol. 2002;71:493–511.

    Article  CAS  PubMed  Google Scholar 

  222. Blonska M, Lin X. NF-κB signaling pathways regulated by CARMA family of scaffold proteins. Cell Res. 2011;21(1):55–70.

    Article  CAS  PubMed  Google Scholar 

  223. Blonska M, et al. CARMA1 controls Th2 cell-specific cytokine expression through regulating JunB and GATA3 transcription factors. J Immunol. 2012;188(7):3160–8.

    Article  CAS  PubMed  Google Scholar 

  224. Hara H, et al. The molecular adapter Carma1 controls entry of IkappaB kinase into the central immune synapse. J Exp Med. 2004;200(9):1167–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Wang D, et al. CD3/CD28 costimulation-induced NF-kappaB activation is mediated by recruitment of protein kinase C-theta, Bcl10, and IkappaB kinase beta to the immunological synapse through CARMA1. Mol Cell Biol. 2004;24(1):164–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Blonska M, et al. The CARMA1-Bcl10 signaling complex selectively regulates JNK2 kinase in the T cell receptor-signaling pathway. Immunity. 2007;26(1):55–66.

    Article  CAS  PubMed  Google Scholar 

  227. Vadlamudi RK, Kumar R. P21-activated kinases in human cancer. Cancer Metastasis Rev. 2003;22(4):385–93.

    Article  CAS  PubMed  Google Scholar 

  228. del Pozo MA, et al. Adhesion to the extracellular matrix regulates the coupling of the small GTPase Rac to its effector PAK. Embo j. 2000;19(9):2008–14.

    Article  PubMed  PubMed Central  Google Scholar 

  229. Chung CY, et al. Role of Rac in controlling the actin cytoskeleton and chemotaxis in motile cells. Proc Natl Acad Sci U S A. 2000;97(10):5225–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Lv Z, et al. Rac1/PAK1 signaling promotes epithelial-mesenchymal transition of podocytes in vitro via triggering beta-catenin transcriptional activity under high glucose conditions. Int J Biochem Cell Biol. 2013;45(2):255–64.

    Article  CAS  PubMed  Google Scholar 

  231. Shi Z, et al. Silencing of HMGA2 promotes apoptosis and inhibits migration and invasion of prostate cancer cells. J Biosci. 2016;41(2):229–36.

    Article  CAS  PubMed  Google Scholar 

  232. Morishita A, et al. HMGA2 is a driver of tumor metastasis. Cancer Res. 2013;73(14):4289–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Thuault S, et al. Transforming growth factor-beta employs HMGA2 to elicit epithelial-mesenchymal transition. J Cell Biol. 2006;174(2):175–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Bianchi ME, Agresti A. HMG proteins: dynamic players in gene regulation and differentiation. Curr Opin Genet Dev. 2005;15(5):496–506.

    Article  CAS  PubMed  Google Scholar 

  235. Deng CX. SIRT1, is it a tumor promoter or tumor suppressor? Int J Biol Sci. 2009;5(2):147–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Palmirotta R, et al. Sirtuins and Cancer: Role in the Epithelial-Mesenchymal Transition. Oxid Med Cell Longev. 2016;2016:3031459.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Jiang W, et al. Functional role of SIRT1-induced HMGB1 expression and acetylation in migration, invasion and angiogenesis of ovarian cancer. Eur Rev Med Pharmacol Sci. 2018;22(14):4431–9.

    CAS  PubMed  Google Scholar 

  238. Brabletz S, Brabletz T. The ZEB/miR-200 feedback loop–a motor of cellular plasticity in development and cancer? EMBO Rep. 2010;11(9):670–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Hurt EM, et al. Expression of the ZEB1 (deltaEF1) transcription factor in human: additional insights. Mol Cell Biochem. 2008;318(1–2):89–99.

    Article  CAS  PubMed  Google Scholar 

  240. Comijn J, et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 2001;7(6):1267–78.

    Article  CAS  PubMed  Google Scholar 

  241. Qu S, et al. Circular RNA: A new star of noncoding RNAs. Cancer Lett. 2015;365(2):141–8.

    Article  CAS  PubMed  Google Scholar 

  242. Meng S, et al. CircRNA: functions and properties of a novel potential biomarker for cancer. Mol Cancer. 2017;16(1):94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  243. Khalili-Tanha G, Moghbeli M. Long non-coding RNAs as the critical regulators of doxorubicin resistance in tumor cells. Cell Mol Biol Lett. 2021;26(1):39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Salzman J, et al. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS ONE. 2012;7(2):e30733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Li X, et al. CircNUP214 sponges miR-145 to promote the expression of ZEB2 in thyroid cancer cells. Biochem Biophys Res Commun. 2018;507(1–4):168–72.

    Article  CAS  PubMed  Google Scholar 

  246. Jung H, et al. TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition. Oncogene. 2008;27(18):2635–47.

    Article  CAS  PubMed  Google Scholar 

  247. Wang LJ, Cai HQ. miR-1258: a novel microRNA that controls TMPRSS4 expression is associated with malignant progression of papillary thyroid carcinoma. Endokrynol Pol. 2020;71(2):146–52.

    Article  CAS  PubMed  Google Scholar 

  248. Westendorp B, et al. E2F7 represses a network of oscillating cell cycle genes to control S-phase progression. Nucleic Acids Res. 2012;40(8):3511–23.

    Article  CAS  PubMed  Google Scholar 

  249. Mitxelena J, et al. An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability. Nucleic Acids Res. 2018;46(9):4546–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Bonavida B, Kaufhold S. Prognostic significance of YY1 protein expression and mRNA levels by bioinformatics analysis in human cancers: a therapeutic target. Pharmacol Ther. 2015;150:149–68.

    Article  CAS  PubMed  Google Scholar 

  251. Lu TX, Li JY, Xu W. The role of SOX11 in mantle cell lymphoma. Leuk Res. 2013;37(11):1412–9.

    Article  CAS  PubMed  Google Scholar 

  252. Chen X, et al. miR-132 Targets FOXA1 and Exerts Tumor-Suppressing Functions in Thyroid Cancer. Oncol Res. 2019;27(4):431–7.

    Article  PubMed  PubMed Central  Google Scholar 

  253. Kinne A, Schülein R, Krause G. Primary and secondary thyroid hormone transporters. Thyroid Res. 2011;4(Suppl 1):S7. Suppl 1.

  254. O’Shea C, et al. Expression of ADAM-9 mRNA and protein in human breast cancer. Int J Cancer. 2003;105(6):754–61.

    Article  PubMed  CAS  Google Scholar 

  255. Smallridge RC, et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012;22(11):1104–39.

    Article  PubMed  Google Scholar 

  256. Kebebew E, et al. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer. 2005;103(7):1330–5.

    Article  PubMed  Google Scholar 

  257. McIver B, et al. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery. 2001;130(6):1028–34.

    Article  CAS  PubMed  Google Scholar 

  258. Mayorca-Guiliani A, Erler JT. The potential for targeting extracellular LOX proteins in human malignancy. Onco Targets Ther. 2013;6:1729–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Li W, et al. Hydrogen peroxide-mediated, lysyl oxidase-dependent chemotaxis of vascular smooth muscle cells. J Cell Biochem. 2000;78(4):550–7.

    Article  CAS  PubMed  Google Scholar 

  260. Giampuzzi M, Oleggini R, Di Donato A. Altered adhesion features and signal transduction in NRK-49F cells transformed by down-regulation of lysyl oxidase. Biochim Biophys Acta. 2003;1647(1–2):239–44.

    Article  CAS  PubMed  Google Scholar 

  261. Payne SL, Hendrix MJ, Kirschmann DA. Paradoxical roles for lysyl oxidases in cancer–a prospect. J Cell Biochem. 2007;101(6):1338–54.

    Article  CAS  PubMed  Google Scholar 

  262. Uddin MH, et al. Involvement of PSMD10, CDK4, and Tumor Suppressors in Development of Intrahepatic Cholangiocarcinoma of Syrian Golden Hamsters Induced by Clonorchis sinensis and N-Nitrosodimethylamine. PLoS Negl Trop Dis. 2015;9(8):e0004008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  263. Narimatsu M, et al. Regulation of planar cell polarity by Smurf ubiquitin ligases. Cell. 2009;137(2):295–307.

    Article  CAS  PubMed  Google Scholar 

  264. Orvedahl A, et al. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature. 2011;480(7375):113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Yamashita M, et al. Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation. Cell. 2005;121(1):101–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

AAH, NT, ZB, and ASZ were involved in search strategy and drafting. MM supervised the project and revised and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Meysam Moghbeli.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hamidi, A.A., Taghehchian, N., Basirat, Z. et al. MicroRNAs as the critical regulators of cell migration and invasion in thyroid cancer. Biomark Res 10, 40 (2022). https://doi.org/10.1186/s40364-022-00382-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s40364-022-00382-4

Keywords

  • Thyroid cancer
  • miRNA
  • Invasion
  • Metastasis
  • Migration
  • Panel marker