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S100A6: molecular function and biomarker role

Biomarker Research volume 11, Article number: 78 (2023) Cite this article

Abstract

S100A6 (also called calcyclin) is a Ca2+-binding protein that belongs to the S100 protein family. S100A6 has many functions related to the cytoskeleton, cell stress, proliferation, and differentiation. S100A6 also has many interacting proteins that are distributed in the cytoplasm, nucleus, cell membrane, and outside the cell. Almost all these proteins interact with S100A6 in a Ca2+-dependent manner, and some also have specific motifs responsible for binding to S100A6. The expression of S100A6 is regulated by several transcription factors (such as c-Myc, P53, NF-κB, USF, Nrf2, etc.). The expression level depends on the specific cell type and the transcription factors activated in specific physical and chemical environments, and is also related to histone acetylation, DNA methylation, and other epigenetic modifications. The differential expression of S100A6 in various diseases, and at different stages of those diseases, makes it a good biomarker for differential diagnosis and prognosis evaluation, as well as a potential therapeutic target. In this review, we mainly focus on the S100A6 ligand and its transcriptional regulation, molecular function (cytoskeleton, cell stress, cell differentiation), and role as a biomarker in human disease and stem cells.

Introduction

S100A6 (also called calcyclin) is a Ca2+-binding protein that belongs to the S100 protein family. Although S100A6 is a cytoplasmic protein, it can be located in the nuclear and cytoplasmic membranes in the presence of Ca2+ [1, 2]. One S100A6 monomer can bind to two Ca2+ ions with different affinities. One Ca2+ binds to the atypical EF-hand loop at the N-terminus of the molecule, and the other Ca2+ binds to the typical EF-hand loop at the C-terminus [3]. The binding of Ca2+ induces a conformational change in S100A6, exposes the hidden hydrophobic region, and induces interactions with the target protein, and Ca2+ signal transduction [4, 5]. So far, many S100A6-interacting proteins have been found, which are distributed in the cytoplasm (such as annexins II, VI, XI, CacyBP/SIP, and Sgt1) [3, 6,7,8,9], nucleus (such as lamin A/C, p53, and FOR20) [10,11,12], cell membranes (such as receptor for advanced glycation end products (RAGE), and integrin β) [13, 14], and extracellular space (such as lumican, and proline/arginine-rich end leucine-rich repeat protein (PRELP)) [15]. S100A6, combined with its ligand, plays an important role in biological processes, such as cytoskeletal function, stress response, cell proliferation, cell differentiation, and signal transduction. S100A6 can also bind to Zn2+; however, the binding site of Zn2+ is different from that of Ca2+ [16]. To date, no research has shown that S100A6 has potential Zn2+-dependent activity.

S100A6 exists in different mammalian cells and tissues, and its expression is substantially increased in fibroblasts and epithelial cells [17]. S100A6 is also expressed in neurons [18], myocardial cells [19], glial cells [20], lymphocytes [21], platelets [22], smooth muscle cells [23], and other cell types. Recent studies have shown that S100A6 is abnormally expressed in various tumor lesions, such as melanoma [24], lung [25], colorectal [26], pancreatic [27], and liver cancers [28]. It plays different regulatory roles in tumor invasion, cell proliferation, and migration, making it a potential therapeutic target. S100A6 is not only expressed in cells but also secreted out of cells [29], and can be detected in various body fluids, such as the extracellular matrix and blood [6]. Therefore, the differential expression of S100A6 in specific diseases makes it a useful biomarker for disease diagnosis and differentiation [30]. This has been one of the lucrative research directions for S100A6 in recent years.

In this review, we mainly focus on the S100A6 ligand and its transcriptional regulation, molecular function (cytoskeleton, cell stress, cell differentiation, etc.), and biomarker role in human diseases and stem cells.

S100A6-interacting proteins

When S100A6 binds to Ca2+, it induces a conformational change resulting in the exposure of hydrophobic surfaces, which are now free to interact with some proteins [4, 5]. Therefore, S100A6 can interact with many proteins distributed in the nucleus, cytoplasm, membrane, and outside of the cell (Table 1), indicating that it has multiple molecular functions. Almost all the interactions with recognized S100A6-interacting proteins are Ca2+-dependent.

Table 1 Subcellular localization of S100A6 ligands
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In the cytoplasm, the previously discovered S100A6-interacting proteins are annexin II, VI, and XI, tropomyosin, caldesmon, calponin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and lysozyme [31,32,33,34,35,36,37,38]. In addition to the unknown functions of GAPDH and lysozyme interacting with S100A6 respectively, the interactions between these proteins and S100A6 in a Ca2+-dependent manner are closely related to the regulation of the actin cytoskeleton and membrane dynamics. CacyBP/SIP is an S100A6 ligand originally purified from Ehrlich ascites tumor cells [7], which was later confirmed to be expressed in all rat tissues at different levels [39]. The modular structure of CacyBP/SIP is important for bringing Siah-1 and Skp1 proteins into the polyubiquitination of β-catenin in the intact SCF-like complex consisting of Skp1, Culin and F-box protein [40]. Sgt1, a suppressor of the G2 allele of Skp1, which is a protein with a 20% homologous sequence to CacyBP/SIP, was originally found in yeast [41]. Therefore, it was speculated to interact with S100A6. This was confirmed by subsequent studies, which found that Sgt1 binds to S100A6, S100A1, S100A4, S100B, and S100P in a Ca2+-dependent manner [42]. Similar to CacyBP/SIP, Sgt1 is widely expressed in different tissues of rats, and its protein and mRNA levels in the brain, skeletal muscle, and spleen are higher than those in other tissues [43]. Some studies have suggested that β-catenin degradation is mediated by the SCF complex, which ubiquitinates the phosphorylated form of β-catenin [44]. Recent studies suggest that β-catenin levels depend on the CacyBP/SIP-Siah1 complex, which ubiquitinates non-phosphorylated β-catenin [9]. Sgt1, which is homologous to CacyBP/SIP, can ubiquitinate yeast proteins Cln1 and Sic1p. Therefore, Sgt1 is believed to affect the function of the ubiquitin ligase complex in mammalian cells [3]. When evaluating the general motif characteristics of S100A6-binding proteins, melusin was found to be similar to CacyBP/SIP and Sgt1, including the CS domain and flexible C-terminal region [3]. Melusin protects cardiac function in a mouse model of chronic hypertension [45]. In recent years, it has been reported that α- and β-tubulin can bind to S100A6 and may participate in the regulation of the cytoskeleton [29]. In addition, S100A6 can also bind to several other cytoplasmic ligand proteins that contain the TPR or CS domains, including FKBP52, cyclophilin 40 (Cyp40), C-terminus of Hsc70-interacting protein (CHIP), protein phosphatase 5) (PP5)FKBP38, Hsp90/Hsp70-organizing protein (Hop), kinesin light chain, and translocase of outer mitochondrial membrane70 (Tom70) [46,47,48].

Several S100A6-interacting proteins are present in the nucleus, such as importin α. Previous studies have shown that S100A6 specifically binds to the armadillo repeats of importin α in a Ca2+-dependent manner, resulting in the formation of importin α complexes in vivo and in vitro and inhibition of the nuclear localization signal (NLS). This suggests that S100A6 may regulate the nuclear transport of NLS-cargo in response to an increase in intracellular Ca2+ concentration [49]. Three p53 family members, namely p53, p63, and p73, are S100A6-interacting proteins; additionally, S100A6 may regulate their transcriptional activity [11, 50]. Lamin A/C, a protein known to be involved in colon cancer [10], interacts with S100A6, which also provides indirect evidence that S100A6 is involved in colon cancer. Recent studies have shown that three centrosomal proteins, FOR20, FOP, and OFD, which are related to cilia formation, also interact with S100A6 in a Ca2+-dependent manner [12].

RAGE and integrin β1 are S100A6-interacting proteins located on the cell membrane. Although S100B and S100A6 have similar structures, they interact with different RAGE extracellular domains. The experimental data showed that S100B and S100A6 have different regulatory effects on cell survival. At micromolar concentrations, S100B promoted cell proliferation, whereas, at the same concentration, S100A6 triggered cell apoptosis. Although the two S100 proteins induce ROS formation, S100B recruits PI3K/AKT and nuclear factor-κB (NF-κB), while S100A6 activates JNK. More importantly, S100B and S100A6 regulate cell survival in a RAGE-dependent manner. S100B specifically interacts with the V and C1 domains of RAGE, while S100A6 specifically interacts with the C1 and C2 domains of RAGE [51]. Another study also showed that the S100A6-binding site is located in the C1 domain of RAGE [52]. This study showed that S100A6 adopts a dimer conformation that is distinct from all known S100 dimers. The combination with S100A6 also induced a unique dimer conformation of RAGE, which seemed to be suitable for signal transduction and recruitment of intracellular effectors [52]. However, some studies indicate that S100A6 interacts with the V domain of RAGE [53]. Further studies are needed to clarify the discrepancy. Similar to other S100A6-interacting proteins, integrin β1 interacts with S100A6 in a Ca2+-dependent manner. The application of an integrin β1-specific antibody reverses the effect of S100A6 on cell adhesion and proliferation [14], which may be due to the blockade of S100A6-integrin interaction. S100A6 protein activates integrin-linked kinase (ILK), focal adhesion kinase (FAK), and p21-activated kinase (PAK) [29].

Three S100A6-interacting proteins, lumican, PRELP, and insulin-like growth factor binding protein 1 (IGFBP-1), were found in the extracellular matrix of Wharton’s jelly in healthy and preeclampsia patients. Lumican and PRELP exist in both healthy patients and preeclampsia patients, while IGFBP-1 only exists in the tissues of preeclampsia patients [15] and may be associated with the development of preeclampsia. The interaction between S100A6 and these proteins is direct, with IGF-1 competing with S100A6 for binding to IGFBP-1 [15].

Regulation of S100A6 transcription

Published data have revealed several transcription factors that regulate S100A6 expression (Fig. 1). Dysfunction of skin keratinocyte differentiation in diabetes is closely related to the impairment of skin barrier function. c-Myc expression is increased in human immortal keratinocytes (HaCaT) cultured in high glucose, diabetic rats, and wound marginal keratinocytes in diabetes patients. High sugar levels, by activating the WNT/β-catenin pathway, increased the expression of c-Myc and inhibited the differentiation of HaCaT cells, while c-Myc combined with the S100A6 promoter directly regulated the expression of S100A6. Inhibition of c-Myc transcriptional activity can alleviate the differentiation dysfunction caused by hyperglycemia or c-Myc overexpression [54]. This suggests that c-Myc and S100A6 are potential therapeutic targets. In the non-metastatic human colorectal cancer cell line SW480, S100A6 was found to be activated by co-transfection of β-catenin and TCF-Lef1 transcription factors [10]. The TCF/LEF family transcription factor domain contains the N-terminal β-catenin-binding domain, which mediates the binding of TCF to β-catenin. Therefore, β-catenin and TCF-Lef1 might activate S100A6 expression after binding.

Fig. 1
figure 1

S100A6 gene structure and transcription factors (based on literature reports)

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P53 is a key regulator of apoptosis and the cell cycle, and S100A6 is believed to be involved in cell-cycle control. Transcriptional regulation experiments in HeLa cells revealed that p53 inhibited the S100A6 promoter in a dose-dependent manner. Inadequate inhibition of this gene by p53 mutants may be responsible for the overexpression of S100A6 and the cell-cycle dysregulation observed in cancer tissues [55]. NF-κB (p65 subunit) strongly induced promoter activity of the porcine S100A6 gene, while the NF-κB inhibitor pyrrolidine dithiocarbamate hampered this activity. In addition, promoters containing mutant NF-κB-binding sites were considerably less active than those containing the wild-type [56].

In addition, the upstream stimulatory factor (USF) can not only binds to the E-box sequence of -283/-278 bits of the S100A6 promoter sequence but also the second E-box motif of -593/-588 bits. The USF1/USF2 heterodimer is the main dimeric form that induces S100A6 transcription [57, 58]. In the oxidative stress model, it was found that the antioxidant response element (ARE) located at the -290/-281 bases of the S100A6 gene promoter overlaps with the E-box sequence recognized by USF, and the mutation of ARE led to the inhibition of Ca2+-stimulated S100A6 promoter activity. In addition to binding to USF, another protein complex, shown by competitive electrophoretic mobility shift assay (EMSA), can bind to ARE. DNA affinity chromatography and western blotting revealed that the Nrf2 transcription factor could bind to the fixed S100A6 gene promoter segment. This indicates that oxidative stress inducers activate S100A6 through the ARE sequence in the promoter [59]. In addition to the regulation by these transcription factors, S100A6 expression is affected by epigenetic modifications such as histone acetylation and DNA methylation [60, 61]. More research is needed to reveal the regulatory mechanism of S100A6 expression.

S100A6 and cytoskeleton

Several studies have shown that some S100 protein family members participate in the regulation of cytoskeleton assembly and degradation [62, 63]. S100A6 is one of the most studied members. Inhibition of S100A6 expression in rat pulmonary fibroblasts weakens cell proliferation, accompanied by flat cell morphology and microfilament destruction marked by tropomyosin [64]; this not only shows that S100A6 is related to the cytoskeleton but also promotes cell proliferation. The S100A6 binding partner cofilin-1 has been found in mouse lung fibroblasts (NIH3T3 cell line) [65]. S100A6 binds to cofilin-1 in a Ca2+-dependent manner, increasing the affinity of cofilin-1 for F-actin and reducing actin filament breakage induced by cofilin-1. In addition, S100A6 stabilizes fibers by inhibiting fiber depolymerization in the presence of cofilin-1. In conclusion, S100A6 regulates actin filament dynamics by controlling the activity of cofilin-1 in a Ca2+-dependent manner [65]. Additionally, S100A6 can directly interact with G-actin and F-actin and preferentially interact with a subtype of tropomyosin (Tpm1.8). S100A6 and tropomyosin bind to the same fiber group and the presence of tropomyosin on the microfilament promotes the binding of S100A6. S100A6 forms complexes with actin and tropomyosin in NIH3T3 cells. These results indicate that S100A6 may regulate the tissue and functional properties of microfilaments through direct interactions with actin and tropomyosin [66].

Osteosarcoma has a high degree of malignancy. Most patients have metastatic or micrometastatic lesions, and metastatic disease is detected in less than 15% when they have clinical manifestations [67]. Some studies have shown that S100A6 is overexpressed in human osteosarcoma. Inhibition of S100A6 expression can inhibit cell adhesion and promote cell migration and invasion. In contrast, S100A6 overexpression can enhance cell adhesion and inhibit cell invasion [68]. The influence of S100A6 on the phenotypes of osteosarcoma cells, such as adhesion, migration, and invasion, may be inextricably related to its cytoskeletal regulation.

Whether actin is present or not, S100A6 will only cross-link with tropomyosin chains in the presence of Ca2+, and the combination of tropomyosin and actin will not lead to the dissociation of tropomyosin [34]. S100 has been shown to regulate the assembly of brain tubulin in vitro and to act on microtubule nucleation and elongation through Ca2+ mediation. This process is also affected by temperature, Ca2+, pH, and in other physical and chemical environments [62]. In addition, myeloid-related protein (MRP)14 (S100A9) and MRP8 (S100A8) interact with the cytoskeleton to perform related functions [69,70,71]. Many members of the S100 family are involved in the regulation of cytoskeleton-related structures and functions. Perhaps the domain shared by the family members is combined with specific cytoskeletal sites, playing a specific role in different time sequences and jointly completing the mission. When evaluating the impact of S100A6 on tumor invasion, migration, and other functions related to the cell bone ring, research on regulating physical and chemical environmental conditions is also valuable and may identify potential therapeutic targets.

S100A6 and cellular stress response

The cellular stress response is a defensive or adaptive response of cells to endogenous or exogenous injury factors. When cells are stimulated by physical and chemical factors, a series of signal transductions occur internally to promote the rapid expression of stress-related molecules and play a role in promoting cell apoptosis or survival. S100A6 participates in the cell stress response, and its expression level increases under oxidative stress [59], hypertension [72], ischemia [73], mechanical stimulation [74], radiation [75], and other stresses.

The Ca2+-dependent interaction with other proteins is critical for S100A6 to perform biological functions. Chaperones are particularly important in cellular stress, especially Hsp90 and Hsp70. Hsp90 and Hsp70 perform the most basic physiological functions in cells, such as protein folding, stretching, transport, oligomer formation, and depolymerization, to maintain cell survival and function. Under adverse conditions such as stress, they can improve the resistance of cells and play a role in stress protection [76, 77]. Hsp90 and Hsp70 are closely bound to chaperone proteins when performing their functions. The chaperoning process is initiated by the interaction between Hsp70 and the client protein, and then the newly formed complex is transferred to the Hsp90-co-chaperone to form a more complex compound (Hsp70-client protein-Hsp90-co-chaperone) called a fold [4].

S100A6 can interact with many of the common partners of Hsp70/ Hsp90, such as kinesin light chain), Hop, Cyp40, Tom70, FKBP52, CHIP, and melusin [3, 7, 42, 46, 48, 78, 79]. This is because their interaction with S100A6 involves the same domain, namely the TPR domain or the CS and/or SGS domain [46, 48, 78, 80]. Although it is clear that S100A6 participates in the cell stress response (Fig. 2), most of the results are from related studies, and the in-depth mechanism needs to be ascertained further.

Fig. 2
figure 2

S100A6 is involved in the regulation of cellular stress response. Cyp40, cyclophilin 40; Hop, Hsp90/Hsp70-organizing protein; Tom70, translocase of outer mitochondrial membrane70

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S100A6 and cell differentiation

The immense diversity of S100 family proteins proves that under various physiological and pathological conditions of cells in the human body, S100 family proteins have multiple biological correlations with cell growth, differentiation, and survival [63]. S100B, a member of the S100 family, is an EF-hand type calcium-binding protein that is widely expressed in astrocytes and participates in the regulation of various intracellular activities, including proliferation and differentiation [81]. Using small interfering RNA technology to reduce the expression level of S100B in the astrocytoma cell line GL15 and the Müller cell line MIO-M1 led to the rapid decomposition of stress fibers; additionally, the collapse and migration of F-actin on the plasma membrane were reduced, and a star shape was acquired. In addition, silencing S100B in GL15 and MIO-M1 cells resulted in more glial fibrillary acidic protein filaments, which marked astrocyte differentiation. These effects depend on S100B interacting with Src kinase to stimulate the PI3K/Akt and PI3K/RhoA pathways [81]. These results suggest that S100B may help reduce the differentiation potential of astrocytes.

As a member of the S100 family, S100A6 has also been found to participate in cell differentiation. Some studies, using an in vitro epidermal differentiation model and stable S100A6 knockout or overexpression HaCaT cells (human immortalized keratinocytes), found that S100A6 mRNA levels decreased significantly during primary keratinocyte differentiation, and that the change in S100A6 expression was not related to DNA methylation but might be affected by epileptogenic factors (ΔNp63 transcription factor and retinoic acid). In conclusion, this study showed that an increase in S100A6 content in keratinocytes significantly changes the speed and degree of epidermal differentiation [82]. HaCaT cells were cultured with high glucose or with keratinocytes from diabetic rats and patients with diabetes, and the expression of S100A6 increased [54]. This occurs because high sugar levels activate the Wnt/β-catenin pathway, which increases the expression of c-Myc, and c-Myc can directly regulate the expression of S100A6 by combining with the S100A6 promoter. The dysfunction of HaCaT cell differentiation caused by overexpression of c-Myc or high glucose can be prevented by knocking out S100A6. These findings suggest that c-Myc upregulation by high glucose inhibits HaCaT differentiation by directly activating S100A6 transcription. Therefore, c-Myc and S100A6 are potential targets for the treatment of chronic diabetic wounds [54].

S100A6 and its family members also participate in the regulation of tumor cell differentiation. Pilomatrixomas are common benign skin tumors containing differentiated hair matrix cells. Although some S100 proteins are expressed in hair follicles in a tissue-specific manner (for example, S100A2 is in the outer root sheath, S100A3 is in the cortex and stratum corneum, and S100A6 is in the inner root sheath), little is known regarding their distribution in trichoblastoma tissues with abnormal differentiation. Immunohistochemistry and double immunofluorescence microscopy were used to detect squamous cells stained with anti-S100A2 antibody, putative root sheath cells, and basophilic and potential hair stromal cells that were occasionally stained. S100A3 staining can be seen in both transitional cells and putative cortical cells and hair-like structures of scattered and surrounding cells (putative keratinocytes). Anti-S100A6 antibody marks some S100A3 negative transitional cell chains, which may be inner root sheath cells [83]. This shows that hair stromal tumors retain a certain degree of differentiation with different hair-forming cells (Fig. 3) [83]. However, the co-expression of S100A6 and MMP9 is related to the progression of skin squamous cell carcinoma [84] and may be involved in some characteristic differentiation of squamous cell carcinoma cells, which needs to be proven. S100A6 is expressed in human osteosarcoma cell lines. Knockdown of S100A6 can improve the osteogenic differentiation activity of mesenchymal stem cells, whereas overexpression of S100A6 inhibits osteogenic differentiation. bone morphogenetic protein 9-induced bone formation is enhanced by S100A6 inhibition. This suggests that S100A6 inhibits the osteogenic differentiation of osteosarcoma [85]. Moreover, S100A6 may participate in thymocyte differentiation [86]. Few studies have examined the relationship between S100A6 expression and cell differentiation. Therefore, knowledge regarding this mechanism is lacking and needs to be complemented with future research. Cell differentiation and proliferation are closely related, whereas S100A6 and cell proliferation are often related to tumor diseases. Therefore, we will introduce S100A6 in combination with cell proliferation and tumor diseases.

Fig. 3
figure 3

Schematic localization of S100A2, S100A3 and S100A6. A Hair matrix cells (some S100A2 positive) proliferated and differentiated into cortical and cuticular cells (S100A3 positive), and the inner root sheath cells (S100A6 positive). Outer root sheath cells (S100A2 positive) surround the hair bulb. Co, cortex of hair; Cu, cuticle of hair; IRS, inner root sheath; ORS, outer root sheath. B Tumour island of pilomatrixoma. Basophil cells (patellar S100A2 positive) divide into adhesion shadow cells (S100A3 positive), transparent shadow cells (S100A6 positive), and possibly columnar or dispersed cuticle cells (S100A3 positive). The outer root sheath cells are inherited by squamous cells (S100A2 positive). (Adapted from reference 83)

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Biomarker role of S100A6

S100A6 as a cancer biomarker

S100A6 is expressed in various tumor diseases, and variations in its expression in different diseases and at different stages of disease development make it a biomarker for disease diagnosis, differentiation, and prognosis evaluation. Accurate diagnosis of thyroid tumors is challenging, and S100A6 plays a potential auxiliary role in the differentiation between follicular thyroid tumors and papillary thyroid carcinomas [87]. The combination (through the decision tree) of the S100 protein family (including S100A6), galectin-3, and its ligand profile can establish an improved identification standard for benign and atypical meningiomas [88]. The unique staining pattern in S100A6 immunohistochemistry may be helpful for the identification of pilar leiomyomas (LM), angeleiomyomas (ALM), and cutaneous leiomyosarcomas (LMS) that are difficult to identify. S100A6 was expressed in some skin smooth muscle tumors and the difference in staining intensity between LM and LMS was statistically significant. A strong S100A6 staining is conducive to the diagnosis of LMS, whereas negative staining supports the diagnosis of LM [89]. Moreover, S100A6 mRNA was significantly elevated in cholangiocarcinoma (CCA), while no significant increase was observed in hepatocellular carcinoma (HCC). The detection of S100A6 mRNA and protein expression levels in tissue samples by northern blotting and immunohistochemical staining may be another useful marker for differentiating between CCA and HCC [90].

S100A6 is closely associated with the prognosis and malignancy of many tumor diseases. The expression of S100A6 in lung squamous cell carcinoma is significantly correlated with patient age and tumor differentiation. S100A6 overexpression is closely related to the poor prognosis of lung squamous cell carcinoma and is considered an independent poor prognostic factor for lung squamous cell carcinoma [91]. In addition, S100A6 is related positively to the invasion of lung adenocarcinoma, especially bronchial adenocarcinoma (BAC). The current results showed that S100A6 immunohistochemistry can be used as a marker to evaluate the malignancy of adenocarcinoma with BAC components [92]. S100A6 and S100A2 are also associated with the progression of thyroid tumors [93]. Although the expression level of S100A6 is significantly increased in human and mouse CCA tumor samples, the serum level of S100A6 is not changed in patients with CCA; therefore, it is not suitable for the diagnosis of CCA. However, compared with patients with low S100A6 levels, CCA patients with elevated S100A6 levels show a trend of impaired prognosis, which supports its use as a biomarker for CCA prognosis [94]. S100A6 may also be a prognostic marker and potential therapeutic target for patients with intrahepatic cholangiocarcinoma (ICC) [95]. MALDI-IMS proteomics has shown that S100A6, S100A10, and thioredoxin can be used for risk stratification of the metastatic potential of papillary thyroid carcinoma [96].

S100A6 not only plays a role in the differential diagnosis, prognosis, and malignant degree prediction of tumor diseases but is also a diagnostic and monitoring indicator of some tumor diseases. Current data show that S100A6 levels increase hierarchically during the occurrence of pancreatic cancer. Measuring the content of S100A6 in pancreatic juice may help identify early pancreatic cancer or high-risk individuals who may develop pancreatic cancer [97]. Moreover, some studies have shown that S100A6 mRNA quantification is a promising diagnostic method and therapeutic target for pancreatic cancer [98]. Serum S100A6 expression is a potential and effective marker for bladder cancer detection. Applying this serum marker to clinical practice can lead to less invasive examinations for patients and help identify life-threatening cancers earlier than current methods [99]. Through proteomic analysis of tumor interstitial fluid, S100A6 was found to be a potential risk marker for screening cholangiocarcinoma [100]; however, it was difficult to obtain test samples. The detection of S100A6 expression levels in gastric cancer tissue and S100A6 detection in serum showed that it has diagnostic and prognostic value and is likely to become a potential therapeutic target [101, 102]. In non–small-cell lung cancer (NSCLC), S100A2 and S100A6 are significantly increased in the early stage and may have potential as biomarkers [103]. S100A6 is also expressed in ovarian and other cancer tissues. The serum concentration of S100A6 was found to be related to the experimental tumor load and clinical disease stage. These data suggest that S100A6 may be useful in detecting and/or monitoring ovarian cancer when used in combination with other biomarkers [104]. In contrast to the increased expression in other tumors, loss of S100A6 protein expression is very common in the development of prostate cancer, which may occur at an early stage. S100A6 expression loss may be a useful diagnostic method for prostate cancer [105].

The expression level of S100A6 in tumors can be used as a biomarker for differentiation, diagnosis, malignancy, and prognosis evaluation (Table 2). However, the detection of S100A6 in tumors must consider whether sample acquisition is simple and feasible and whether serological detection is more feasible. Most of the research results need to be verified by a large cohort and multicenter research. S100A6 is expected to bring about novel changes in the diagnosis and treatment of tumor diseases.

Table 2 S100A6’s biomarker role in tumor diseases
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Biomarker role of S100A6 in stem cells

Stem cells exist in various tissues of the body, and their location is called a niche. Stem cells can proliferate and differentiate into offspring of some special cell types and are the cell source needed for tissue maintenance and regeneration. Owing to its potential to repair tissue damage, it is the focus of tissue engineering and other regenerative repair research. However, stem cells are scarce and lack universal markers, making their isolation and identification difficult [30]. In recent years, the development of various omics technologies has helped to promote stem cell-related research. Increasing evidence shows that S100A6 is expressed in various stem cells and has the potential to become a biomarker.

Epidermal stem cells (ESCs) mainly exist in the basal layer of the interfollicular epidermis (IFE) and hair follicle bulge area under the sebaceous gland [106]. Epidermal cells, also known as keratinocytes, serve as barriers against direct contact with the external environment, shedding and renewing periodically. S100A6 protein and mRNA have been found to exist in the mouse hair follicle bulge area and outer root sheath (adjacent to the bulge) [107]. Similarly, microarray analysis showed that fluorescence-activated cell sorting (FACS) based on fluorescence labeling enriched S100A6 gene expression in label-retaining cells (LRC) isolated from the skin of transgenic mice [108]. Wnt-10b can also promote skin-derived CD34 and CD49f double-positive cells (enriched epithelial stem cells or progenitor cells) to express classical markers of bulge stem cells, including S100A6, Lhx2, Keratin15, Sox9, and NFATc1 [109]. With the development of single-cell sequencing technology, evidence of S100A6 expression in mouse hair follicle bulge cells and the basal layer of the hair follicle inner epidermis is more abundant [110, 111]. These findings have led researchers to list S100A6 as a marker for epidermal stem cells.

Mesenchymal stem cells (MSCs) exist in the connective tissue and organ stroma, with the bone marrow being the most abundant reservoir. Because the bone marrow is the main source of MSCs, they are also called bone marrow mesenchymal stem cells. Mesenchymal stem cells can express specific molecules and differentiate into osteoblasts, adipocytes, and chondrocytes in vitro [112]. Single-cell sequencing (scRNA-seq) has shown that S100A6 expression is upregulated in human synovial fluid-derived mesenchymal stem cells (hSF MSCs) [113]. Additionally, published literature shows that S100A6 can be secreted by Wharton’s jelly mesenchymal stem cells and is associated with integrin β1 binding to activate ILK, FAK, and PAK [29]. This suggests that S100A6 may be a marker of mesenchymal stem cells.

According to current knowledge, there are mainly two regions of neural stem cells in the brain of adult mice: the subventricular zone (SVZ) near the lateral ventricles of the forebrain, and the subgranular layer of the dentate gyrus of the hippocampal formation [30]. Some studies have shown that S100A6 is highly expressed in neural stem cells labeled with the sex-determining region Y-box 2, brain lipid-binding protein, and glial fibrillary acidic protein by immunofluorescence multiple labeling. It was also shown for the first time that S100A6 is a specific marker of neural stem cells and astrocyte precursors and may also be particularly important for the generation of astrocytes in the adult hippocampus [114]. It has also been found that most of the sox2-positive cells located in the dentate gyrus (DG) of mice express S100A6 at the same time [115]. In addition, S100A6 immunostaining is higher in the subependymal zone (SEZ) but lower in the medial subependymal zone (MEZ) [116].

The surfaces and cavities of internal organs are covered by epithelial cells. The intestinal epithelium has strong regenerative and fast renewal abilities. The base of the intestinal crypt is considered the niche of intestinal stem cells (ISCs) and the source of new intestinal epithelial cells. However, owing to the rapid renewal of the intestinal epithelium, the proliferation of cells in the crypt has always been active, and its real reserve intestinal stem cells have proven difficult to establish [117]. Through pedigree tracking, it was found that Lgr5-expressing cell derivatives contain radiation-resistant ISCs, which are crucial for the regeneration of irradiated intestinal epithelium [118]. S100A6 was found to be expressed in mouse resting intestinal stem cells that survived whole-body irradiation and were able to reconstruct the intestinal epithelium [118].

The “cancer stem cell hypothesis” has two main concepts: one is that tumors originate from tissue stem cells or their direct progeny cells because the self-renewal process that is strictly regulated under normal circumstances is out of balance; second, the tumor contains a kind of cell sub-component, which retains the key stem cell characteristics. These characteristics include self-renewal, which drives tumorigenesis and abnormal differentiation, leading to cellular heterogeneity [119]. Although this hypothesis has been put forward for more than 150 years, it has not received increasing attention in the field of cancer research until progress in cancer stem cell biology has been made in recent years. As a common abnormally expressed gene in tumors, S100A6 has been found in the lateral population of cancer stem cells (CSCs) isolated from brain tumors of transgenic mice forming glioma mouse models [120]. Gene expression analysis showed a 31.5-fold increase in S100A6 gene expression (and a 14.7-fold increase in S100A4 gene expression) in these cells compared with most tumor cells. Immunofluorescence staining confirmed the presence of S100A6 and S100A4 proteins in the cancer subpopulation of primary human glioma, and their abundance was correlated with tumor grade [120]. Some studies have isolated and identified breast CSCs through tumor ball culture, identified the changes in protein expression in CSCs compared with non-CSCs using LC–MS/MS, and identified a group of differential genes (PTMA, S100A4, TNXRD1, COX-1, COX-2, KRT14, and FTH1), representing possible molecular targets [121]. CSCs exhibit self-renewal, pluripotency, tumor initiation after transplantation, and resistance to radiotherapy or chemotherapy drugs, which may be the cause of cancer recurrence. Therefore, research on CSCs is of great significance to improve the understanding and diagnosis of cancer.

Hematopoietic stem cells (HSCs) located in the bone marrow can differentiate into various lineages of blood cells [122]. After continuous differentiation, HSCs enter the multipotent progenitor (MPPs) stage and then differentiate into precursors of two blood cell lineages: common lymphoid progenitors (CLP) or common myeloid progenitors (CMP). After a series of differentiations, the former becomes T and B lymphocytes or natural killer cells (NK), while the latter becomes monocytes, granulocytes, red blood cells, and megakaryocytes [122]. However, S100A6 knockout HSCs reduced the total number of HSC in the HSC chamber, reduced the output of the myeloid system, and increased the number of apoptotic HSCs in the stable state [123]. This indicates that S100A6-knockout HSCs have impaired self-renewal and regeneration capacities. Transcriptional and proteomic analyses have shown that S100A6 is a key HSC regulator. Activation of the Akt pathway is the main mechanism of S100A6 promoting HSCs self-renewal via regulation of mitochondrial metabolic function and Hsp90 protein quality [123].

Immunohistochemistry, RT-PCR, and scRNA-seq techniques revealed the expression of S100A6 in epidermal, neural, cancer, hematopoietic, and epithelial stem cells (Table 3). These data indicate that S100A6 is closely related to cellular stemness. However, there are few studies on S100A6 as a marker for stem cell identification and characterization, and more research is needed.

Table 3 S100A6’s biomarker role in stem cells
Full size table

Biomarker role of S100A6 in other diseases

S100A6 is expressed in tumor diseases and stem cells and has a potential biomarker role. S100A6 has similar functions in other diseases. Serum calumin, S100A6, and cytokinin 2 have been confirmed as biomarkers in patients with systemic sclerosis with skin involvement, and S100A6 is related to the number of active digital ulcers [124]. Another study used a functional proteomic approach to analyze bronchoalveolar lavage samples from patients with pulmonary fibrosis systemic sclerosis (PF-SSc), smokers, and nonsmokers. The MetaCore network of this study suggests the use of C3a, APOAI, 14–3-3e, SPFA2, and S100A6 as potential biomarkers. These upstream molecules are involved in pulmonary fibrosis, innate immunity, and vascular injury in PF-SSc patients [125]. In addition, in a transgenic mouse model of amyotrophic lateral sclerosis (ALS), it was found that reactive astrocytes (not motor neurons) highly expressed S100A6 in several regions (including 12 pairs of nerve roots) in the brain stem, while S100A6 was negative in the sublingual nucleus. However, in the dorsal root, the reactive astrocytes from the white matter and the anterior horn were highly reactive [126]. Therefore, the overexpression of S100A6 is considered a valuable diagnostic marker for ALS [126]. Specific expression of S100A6 in many diseases results in its rich functional characteristics. Revealing its function in specific diseases is of great significance for understanding and diagnosing related diseases.

Conclusions

S100A6 belongs to the S100 protein family, and is a calcium-binding protein. S100A6 has numerous molecular functions related to the cytoskeleton, cell stress, cell proliferation, and cell differentiation. S100A6 also has many interacting proteins that are distributed in the cytoplasm, nucleus, cell membrane, and outside the cell. Almost all these proteins interact with S100A6 in a Ca2+-dependent manner, and some also have a specific motif, which is responsible for binding to S100A6 to initiate biological effects. The expression of S100A6 is regulated by several transcription factors (such as c-Myc, P53, NF-κB, USF, Nrf2, etc.). The level of S100A6 expression depends on the specific cell type and activated transcription factors in specific physical and chemical environments, and is also related to epigenetic modifications, such as histone acetylation and DNA methylation.

S100A6 can be used as a biomarker for diagnosis, differential diagnosis, and prognosis evaluation because of its differential expression in various diseases and at different stages of the same disease. In tumor diseases, it is also related to the degree of malignancy and can be used to monitor related diseases and as a potential therapeutic target. S100A6 can be used not only as a biomarker of disease but also as a biomarker of stem cells. Stem cells are the source of cells needed for tissue maintenance and regeneration, and have the potential to repair tissue damage. They are the research focus in tissue engineering and other regeneration and repair fields. However, stem cells are scarce and lack universal markers, making their isolation and identification difficult. With the development of various omics technologies, increasing evidence has shown that S100A6 is expressed in various stem cells and is a promising biomarker that may aid in carrying out stem cell-related work.

S100A6 is a key molecule in the body and is involved in many pathophysiological processes. Its differential expression in normal tissues or diseases, especially in various diseases or at different stages of the same disease, gives it the functional characteristics of biomarkers. It also has the potential to be a target for the treatment of some diseases. The increasing interest in S100A6 may help improve the understanding of these diseases and advance diagnostic and treatment methods.

Availability of data and materials

Not applicable.

Abbreviations

RAGE :

Receptor for advanced glycation end products

PRELP:

Proline/arginine-rich end leucine-rich repeat protein

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

Cyp40:

Cyclophilin 40

CHIP:

C-terminus of Hsc70-interacting protein

PP5:

Protein phosphatase 5

Hop:

Hsp90/Hsp70-organizing protein

Tom70:

Translocase of outer mitochondrial membrane70

NLS:

Nuclear localization signal

IGFBP-1:

Insulin-like growth factor binding protein 1

ARE:

Antioxidant response element

EMSA:

Electrophoretic mobility shift assay

LM:

Leiomyomas

ALM:

Angeleiomyomas

LMS:

Leiomyosarcomas

CCA :

Cholangiocarcinoma

HCC:

Hepatocellular carcinoma

BAC:

Bronchial adenocarcinoma

ICC:

Intr ahepatic cholangiocarcinoma

NSCLC:

Non–small-cell lung cancer

ESCs:

Epidermal stem cells

IFE:

Interfollicular epidermis

FACS:

Fluorescence-activated cell sorting

LRC:

Label-retaining cells

MSCs:

Mesenchymal stem cells

scRNA-seq:

Single-cell sequencing

hSF MSCs:

Human synovial fluid-derived mesenchymal stem cells

SVZ:

Subventricular zone

DG:

Dentate gyrus

MEZ:

Medial subependymal zone

ISCs:

Intestinal stem cells

CSCs:

Cancer stem cells

HSCs:

Hematopoietic stem cells

MPPs:

Multipotent progenitor stage

CLP:

Common lymphoid progenitors

CMP:

Common myeloid progenitors

NK:

Natural killer

References

  1. Lesniak W, Filipek A. Ca2+-dependent interaction of calcyclin with membrane. Biochem Biophys Res Commun. 1996;220(2):269–73.

    CAS  PubMed  Google Scholar 

  2. Stradal TB, Gimona M. Ca(2+)-dependent association of S100A6 (Calcyclin) with the plasma membrane and the nuclear envelope. J Biol Chem. 1999;274(44):31593–6.

    CAS  PubMed  Google Scholar 

  3. Filipek A, Michowski W, Kuznicki J. Involvement of S100A6 (calcyclin) and its binding partners in intracellular signaling pathways. Adv Enzyme Regul. 2008;48:225–39.

    CAS  PubMed  Google Scholar 

  4. Filipek A, Leśniak W. Current view on cellular function of S100A6 and its ligands, CacyBP/SIP and Sgt1. Postepy Biochem. 2018;64(3):242–52.

    PubMed  Google Scholar 

  5. Sastry M, Ketchem RR, Crescenzi O, et al. The three-dimensional structure of Ca(2+)-bound calcyclin: implications for Ca(2+)-signal transduction by S100 proteins. Structure. 1998;6(2):223–31.

    CAS  PubMed  Google Scholar 

  6. Leśniak W, Słomnicki ŁP, Filipek A. S100A6 - new facts and features. Biochem Biophys Res Commun. 2009;390(4):1087–92.

    PubMed  Google Scholar 

  7. Filipek A, Wojda U. p30, a novel protein target of mouse calcyclin (S100A6). Biochem J. 1996;320 (Pt 2)(Pt 2):585–7.

    PubMed  Google Scholar 

  8. Filipek A, Kuźnicki J. Molecular cloning and expression of a mouse brain cDNA encoding a novel protein target of calcyclin. J Neurochem. 1998;70(5):1793–8.

    CAS  PubMed  Google Scholar 

  9. Matsuzawa SI, Reed JC. Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Mol Cell. 2001;7(5):915–26.

    CAS  PubMed  Google Scholar 

  10. Kilańczyk E, Graczyk A, Ostrowska H, Kasacka I, Leśniak W, Filipek A. S100A6 is transcriptionally regulated by β-catenin and interacts with a novel target, lamin A/C, in colorectal cancer cells. Cell Calcium. 2012;51(6):470–7.

    PubMed  Google Scholar 

  11. Słomnicki ŁP, Nawrot B, Leśniak W. S100A6 binds p53 and affects its activity. Int J Biochem Cell Biol. 2009;41(4):784–90.

    PubMed  Google Scholar 

  12. Sakane K, Nishiguchi M, Denda M, et al. Identification and characterization of a centrosomal protein, FOR20 as a novel S100A6 target. Biochem Biophys Res Commun. 2017;491(4):980–5.

    CAS  PubMed  Google Scholar 

  13. Khan MI, Dowarha D, Katte R, Chou RH, Filipek A, Yu C. Lysozyme as the anti-proliferative agent to block the interaction between S100A6 and the RAGE V domain. PLoS One. 2019;14(5):e0216427.

    PubMed  PubMed Central  Google Scholar 

  14. Jurewicz E, Góral A, Filipek A. S100A6 is secreted from Wharton’s jelly mesenchymal stem cells and interacts with integrin β1. Int J Biochem Cell Biol. 2014;55:298–303.

    CAS  PubMed  Google Scholar 

  15. Jurewicz E, Kasacka I, Bankowski E, Filipek A. S100A6 and its extracellular targets in Wharton’s jelly of healthy and preeclamptic patients. Placenta. 2014;35(6):386–91.

    CAS  PubMed  Google Scholar 

  16. Filipek A, Heizmann CW, Kuźnicki J. Calcyclin is a calcium and zinc binding protein. FEBS Lett. 1990;264(2):263–6.

    CAS  PubMed  Google Scholar 

  17. Kuźnicki J, Kordowska J, Puzianowska M, Woźniewicz BM. Calcyclin as a marker of human epithelial cells and fibroblasts. Exp Cell Res. 1992;200(2):425–30.

    PubMed  Google Scholar 

  18. Filipek A, Puzianowska M, Cieślak B, Kuźnicki J. Calcyclin–Ca(2+)-binding protein homologous to glial S-100 beta is present in neurones. NeuroReport. 1993;4(4):383–6.

    CAS  PubMed  Google Scholar 

  19. Engelkamp D, Schäfer BW, Erne P, Heizmann CW. S100 alpha, CAPL, and CACY: molecular cloning and expression analysis of three calcium-binding proteins from human heart. Biochemistry. 1992;31(42):10258–64.

    CAS  PubMed  Google Scholar 

  20. Yamashita N, Ilg EC, Schäfer BW, Heizmann CW, Kosaka T. Distribution of a specific calcium-binding protein of the S100 protein family, S100A6 (calcyclin), in subpopulations of neurons and glial cells of the adult rat nervous system. J Comp Neurol. 1999;404(2):235–57.

    CAS  PubMed  Google Scholar 

  21. Ferrari S, Tagliafico E, Manfredini R, et al. Abundance of the primary transcript and its processed product of growth-related genes in normal and leukemic cells during proliferation and differentiation. Cancer Res. 1992;52(1):11–6.

    CAS  PubMed  Google Scholar 

  22. Tomida Y, Terasawa M, Kobayashi R, Hidaka H. Calcyclin and calvasculin exist in human platelets. Biochem Biophys Res Commun. 1992;189(3):1310–6.

    CAS  PubMed  Google Scholar 

  23. Mandinova A, Atar D, Schäfer BW, Spiess M, Aebi U, Heizmann CW. Distinct subcellular localization of calcium binding S100 proteins in human smooth muscle cells and their relocation in response to rises in intracellular calcium. J Cell Sci. 1998;111(Pt 14):2043–54.

    CAS  PubMed  Google Scholar 

  24. Mitamura Y, Ito T, Nakano-Nakamura M, Uchi H, Furue M. S100A6 and c-Kit-positive spindle cell melanoma of the dorsal foot. Case Rep Dermatol. 2014;6(2):140–4.

    PubMed  PubMed Central  Google Scholar 

  25. Wang T, Han S, Du G. S100A6 represses Calu-6 lung cancer cells growth via inhibiting cell proliferation, migration, invasion and enhancing apoptosis. Cell Biochem Funct. 2021;39(6):771–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang XH, Du H, Li L, et al. Increased expression of S100A6 promotes cell proliferation in gastric cancer cells. Oncol Lett. 2017;13(1):222–30.

    CAS  PubMed  Google Scholar 

  27. Zihao G, Jie Z, Yan L, et al. Analyzing S100A6 expression in endoscopic ultrasonography-guided fine-needle aspiration specimens: a promising diagnostic method of pancreatic cancer. J Clin Gastroenterol. 2013;47(1):69–75.

    PubMed  Google Scholar 

  28. Song D, Xu B, Shi D, Li S, Cai Y. S100A6 promotes proliferation and migration of HepG2 cells via increased ubiquitin-dependent degradation of p53. Open Med (Wars). 2020;15(1):317–26.

    CAS  PubMed  Google Scholar 

  29. Jurewicz E, Wyroba E, Filipek A. Tubulin-dependent secretion of S100A6 and cellular signaling pathways activated by S100A6-integrin β1 interaction. Cell Signal. 2018;42:21–9.

    CAS  PubMed  Google Scholar 

  30. Leśniak W, Filipek A. S100A6 as a constituent and potential marker of adult and cancer stem cells. Stem Cell Rev Rep. 2022;18(8):2699–708.

    PubMed  Google Scholar 

  31. Filipek A, Gerke V, Weber K, Kuźnicki J. Characterization of the cell-cycle-regulated protein calcyclin from Ehrlich ascites tumor cells. Identification of two binding proteins obtained by Ca2(+)-dependent affinity chromatography. Eur J Biochem. 1991;195(3):795–800.

    CAS  PubMed  Google Scholar 

  32. Tokumitsu H, Kobayashi R, Hidaka H. A calcium-binding protein from rabbit lung cytosol identified as the product of growth-regulated gene (2A9) and its binding proteins. Arch Biochem Biophys. 1991;288(1):202–7.

    CAS  PubMed  Google Scholar 

  33. Zeng FY, Gerke V, Gabius HJ. Identification of annexin II, annexin VI and glyceraldehyde-3-phosphate dehydrogenase as calcyclin-binding proteins in bovine heart. Int J Biochem. 1993;25(7):1019–27.

    CAS  PubMed  Google Scholar 

  34. Golitsina NL, Kordowska J, Wang CL, Lehrer SS. Ca2+-dependent binding of calcyclin to muscle tropomyosin. Biochem Biophys Res Commun. 1996;220(2):360–5.

    CAS  PubMed  Google Scholar 

  35. Filipek A, Zasada A, Wojda U, Makuch R, Dabrowska R. Characterization of chicken gizzard calcyclin and examination of its interaction with caldesmon. Comp Biochem Physiol B Biochem Mol Biol. 1996;113(4):745–52.

    CAS  PubMed  Google Scholar 

  36. Mani RS, Kay CM. Isolation and characterization of a novel molecular weight 11,000 Ca2(+)-binding protein from smooth muscle. Biochemistry. 1990;29(6):1398–404.

    CAS  PubMed  Google Scholar 

  37. Wills FL, McCubbin WD, Kay CM. Smooth muscle calponin-caltropin interaction: effect on biological activity and stability of calponin. Biochemistry. 1994;33(18):5562–9.

    CAS  PubMed  Google Scholar 

  38. Filipek A, Wojda U. Chicken gizzard calcyclin–distribution and potential target proteins. Biochem Biophys Res Commun. 1996;225(1):151–4.

    CAS  PubMed  Google Scholar 

  39. Jastrzebska B, Filipek A, Nowicka D, Kaczmarek L, Kúznicki J. Calcyclin (S100A6) binding protein (CacyBP) is highly expressed in brain neurons. J Histochem Cytochem. 2000;48(9):1195–202.

    CAS  PubMed  Google Scholar 

  40. Bhattacharya S, Lee YT, Michowski W, et al. The modular structure of SIP facilitates its role in stabilizing multiprotein assemblies. Biochemistry. 2005;44(27):9462–71.

    CAS  PubMed  Google Scholar 

  41. Kitagawa K, Skowyra D, Elledge SJ, Harper JW, Hieter P. SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex. Mol Cell. 1999;4(1):21–33.

    CAS  PubMed  Google Scholar 

  42. Nowotny M, Spiechowicz M, Jastrzebska B, Filipek A, Kitagawa K, Kuznicki J. Calcium-regulated interaction of Sgt1 with S100A6 (calcyclin) and other S100 proteins. J Biol Chem. 2003;278(29):26923–8.

    CAS  PubMed  Google Scholar 

  43. Spiechowicz M, Filipek A. The expression and function of Sgt1 protein in eukaryotic cells. Acta Neurobiol Exp (Wars). 2005;65(2):161–5.

    PubMed  Google Scholar 

  44. Zheng N, Schulman BA, Song L, et al. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 2002;416(6882):703–9.

    CAS  PubMed  Google Scholar 

  45. De Acetis M, Notte A, Accornero F, et al. Cardiac overexpression of melusin protects from dilated cardiomyopathy due to long-standing pressure overload. Circ Res. 2005;96(10):1087–94.

    PubMed  Google Scholar 

  46. Shimamoto S, Kubota Y, Tokumitsu H, Kobayashi R. S100 proteins regulate the interaction of Hsp90 with Cyclophilin 40 and FKBP52 through their tetratricopeptide repeats. FEBS lett. 2010;584(6):1119–25.

    CAS  PubMed  Google Scholar 

  47. Shimamoto S, Tsuchiya M, Yamaguchi F, Kubota Y, Tokumitsu H, Kobayashi R. Ca2+/S100 proteins inhibit the interaction of FKBP38 with Bcl-2 and Hsp90. Biochem J. 2014;458(1):141–52.

    CAS  PubMed  Google Scholar 

  48. Yamaguchi F, Umeda Y, Shimamoto S, et al. S100 proteins modulate protein phosphatase 5 function: a link between CA2+ signal transduction and protein dephosphorylation. J Biol Chem. 2012;287(17):13787–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Takata M, Shimamoto S, Yamaguchi F, Tokuda M, Tokumitsu H, Kobayashi R. Regulation of nuclear localization signal-importin α interaction by Ca2+/S100A6. FEBS lett. 2010;584(22):4517–23.

    CAS  PubMed  Google Scholar 

  50. van Dieck J, Brandt T, Teufel DP, Veprintsev DB, Joerger AC, Fersht AR. Molecular basis of S100 proteins interacting with the p53 homologs p63 and p73. Oncogene. 2010;29(14):2024–35.

    PubMed  Google Scholar 

  51. Leclerc E, Fritz G, Weibel M, Heizmann CW, Galichet A. S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. J Biol Chem. 2007;282(43):31317–31.

    CAS  PubMed  Google Scholar 

  52. Yatime L, Betzer C, Jensen RK, Mortensen S, Jensen PH, Andersen GR. The Structure of the RAGE:S100A6 complex reveals a unique mode of homodimerization for S100 proteins. Structure. 2016;24(12):2043–52.

    CAS  PubMed  Google Scholar 

  53. Mohan SK, Gupta AA, Yu C. Interaction of the S100A6 mutant (C3S) with the V domain of the receptor for advanced glycation end products (RAGE). Biochem Biophys Res Commun. 2013;434(2):328–33.

    CAS  PubMed  Google Scholar 

  54. Zhang J, Yang P, Liu D, et al. c-Myc upregulated by high glucose inhibits HaCaT differentiation by S100A6 transcriptional activation. Front Endocrinol (Lausanne). 2021;12:676403.

    PubMed  PubMed Central  Google Scholar 

  55. Króliczak W, Pietrzak M, Puzianowska-Kuznicka M. P53-dependent suppression of the human calcyclin gene (S100A6): the role of Sp1 and of NFkappaB. Acta Biochim Pol. 2008;55(3):559–70.

    PubMed  Google Scholar 

  56. Zhou X, Wang P, Michal JJ, et al. Molecular characterization of the porcine S100A6 gene and analysis of its expression in pigs infected with highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV). J Appl Genet. 2015;56(3):355–63.

    CAS  PubMed  Google Scholar 

  57. Leśniak W, Kuźnicki J. Binding and functional characteristics of two E-box motifs within the S100A6 (calcyclin) gene promoter. J Cell Biochem. 2006;97(5):1017–24.

    PubMed  Google Scholar 

  58. Leśniak W, Jezierska A, Kuźnicki J. Upstream stimulatory factor is involved in the regulation of the human calcyclin (S100A6) gene. Biochim Biophys Acta. 2000;1517(1):73–81.

    PubMed  Google Scholar 

  59. Leśniak W, Szczepańska A, Kuźnicki J. Calcyclin (S100A6) expression is stimulated by agents evoking oxidative stress via the antioxidant response element. Biochim Biophys Acta. 2005;1744(1):29–37.

    PubMed  Google Scholar 

  60. Leśniak W, Słomnicki ŁP, Kuźnicki J. Epigenetic control of the S100A6 (calcyclin) gene expression. J Invest Dermatol. 2007;127(10):2307–14.

    PubMed  Google Scholar 

  61. Leśniak W, Swart GW, Bloemers HP, Kuźnicki J. Regulation of cell specific expression of calcyclin (S100A6) in nerve cells and other tissues. Acta Neurobiol Exp (Wars). 2000;60(4):569–75.

    PubMed  Google Scholar 

  62. Donato R. Quantitative analysis of the interaction between S-100 proteins and brain tubulin. Cell Calcium. 1987;8(4):283–97.

    CAS  PubMed  Google Scholar 

  63. Gross SR, Sin CG, Barraclough R, Rudland PS. Joining S100 proteins and migration: for better or for worse, in sickness and in health. Cell Mol Life Sci. 2014;71(9):1551–79.

    CAS  PubMed  Google Scholar 

  64. Breen EC, Tang K. Calcyclin (S100A6) regulates pulmonary fibroblast proliferation, morphology, and cytoskeletal organization in vitro. J Cell Biochem. 2003;88(4):848–54.

    CAS  PubMed  Google Scholar 

  65. Robaszkiewicz K, Jurewicz E, Moraczewska J, Filipek A. Ca(2+)-dependent binding of S100A6 to cofilin-1 regulates actin filament polymerization-depolymerization dynamics. Cell Calcium. 2021;99:102457.

    CAS  PubMed  Google Scholar 

  66. Jurewicz E, Robaszkiewicz K, Moraczewska J, Filipek A. Binding of S100A6 to actin and the actin-tropomyosin complex. Sci Rep. 2020;10(1):12824.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Luu HH, Zhou L, Haydon RC, et al. Increased expression of S100A6 is associated with decreased metastasis and inhibition of cell migration and anchorage independent growth in human osteosarcoma. Cancer lett. 2005;229(1):135–48.

    CAS  PubMed  Google Scholar 

  68. Luo X, Sharff KA, Chen J, He TC, Luu HH. S100A6 expression and function in human osteosarcoma. Clin Orthop Relat Res. 2008;466(9):2060–70.

    PubMed  PubMed Central  Google Scholar 

  69. Roth J, Burwinkel F, van den Bos C, Goebeler M, Vollmer E, Sorg C. MRP8 and MRP14, S-100-like proteins associated with myeloid differentiation, are translocated to plasma membrane and intermediate filaments in a calcium-dependent manner. Blood. 1993;82(6):1875–83.

    CAS  PubMed  Google Scholar 

  70. Goebeler M, Roth J, van den Bos C, Ader G, Sorg C. Increase of calcium levels in epithelial cells induces translocation of calcium-binding proteins migration inhibitory factor-related protein 8 (MRP8) and MRP14 to keratin intermediate filaments. Biochem J. 1995;309 (Pt 2)(Pt 2):419–24.

    PubMed  Google Scholar 

  71. Vogl T, Ludwig S, Goebeler M, et al. MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood. 2004;104(13):4260–8.

    CAS  PubMed  Google Scholar 

  72. Kasacka I, Piotrowska Ż, Filipek A, Majewski M. Influence of doxazosin on biosynthesis of S100A6 and atrial natriuretic factor peptides in the heart of spontaneously hypertensive rats. Exp Biol Med (Maywood). 2016;241(4):375–81.

    CAS  PubMed  Google Scholar 

  73. Lewington AJ, Padanilam BJ, Hammerman MR. Induction of calcyclin after ischemic injury to rat kidney. Am J Physiol. 1997;273(3 Pt 2):F380-385.

    CAS  PubMed  Google Scholar 

  74. Breen EC, Fu Z, Normand H. Calcyclin gene expression is increased by mechanical strain in fibroblasts and lung. Am J Respir Cell Mol Biol. 1999;21(6):746–52.

    CAS  PubMed  Google Scholar 

  75. Orre LM, Pernemalm M, Lengqvist J, Lewensohn R, Lehtiö J. Up-regulation, modification, and translocation of S100A6 induced by exposure to ionizing radiation revealed by proteomics profiling. Mol Cell Proteomics. 2007;6(12):2122–31.

    CAS  PubMed  Google Scholar 

  76. Li J, Soroka J, Buchner J. The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta. 2012;1823(3):624–35.

    CAS  PubMed  Google Scholar 

  77. Johnson JL. Evolution and function of diverse Hsp90 homologs and cochaperone proteins. Biochim Biophys Acta. 2012;1823(3):607–13.

    CAS  PubMed  Google Scholar 

  78. Shimamoto S, Takata M, Tokuda M, Oohira F, Tokumitsu H, Kobayashi R. Interactions of S100A2 and S100A6 with the tetratricopeptide repeat proteins, Hsp90/Hsp70-organizing protein and kinesin light chain. J Biol Chem. 2008;283(42):28246–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Sbroggiò M, Ferretti R, Percivalle E, et al. The mammalian CHORD-containing protein melusin is a stress response protein interacting with Hsp90 and Sgt1. FEBS lett. 2008;582(13):1788–94.

    PubMed  Google Scholar 

  80. Lee YT, Jacob J, Michowski W, Nowotny M, Kuznicki J, Chazin WJ. Human Sgt1 binds HSP90 through the CHORD-Sgt1 domain and not the tetratricopeptide repeat domain. J Biol Chem. 2004;279(16):16511–7.

    CAS  PubMed  Google Scholar 

  81. Brozzi F, Arcuri C, Giambanco I, Donato R. S100B protein regulates astrocyte shape and migration via interaction with Src kinase: implications for astrocyte development, activation, and tumor growth. J Biol Chem. 2009;284(13):8797–811.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Graczyk A, Leśniak W. S100A6 expression in keratinocytes and its impact on epidermal differentiation. Int J Biochem Cell Biol. 2014;57:135–41.

    CAS  PubMed  Google Scholar 

  83. Kizawa K, Toyoda M, Ito M, Morohashi M. Aberrantly differentiated cells in benign pilomatrixoma reflect the normal hair follicle: immunohistochemical analysis of Ca-binding S100A2, S100A3 and S100A6 proteins. Br J Dermatol. 2005;152(2):314–20.

    CAS  PubMed  Google Scholar 

  84. Zhu L, Kohda F, Nakahara T, et al. Aberrant expression of S100A6 and matrix metalloproteinase 9, but not S100A2, S100A4, and S100A7, is associated with epidermal carcinogenesis. J Dermatol Sci. 2013;72(3):311–9.

    CAS  PubMed  Google Scholar 

  85. Li Y, Wagner ER, Yan Z, et al. The calcium-binding protein S100A6 accelerates human osteosarcoma growth by promoting cell proliferation and inhibiting osteogenic differentiation. Cell Physiol Biochem. 2015;37(6):2375–92.

    CAS  PubMed  Google Scholar 

  86. Jeon CH, Kim HL, Park JH. Induction of S100A4, S100A6, and galectin-1 during the lineage commitment of CD4+CD8+ thymocyte cell line is suppressed by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Lett. 2009;187(3):157–63.

    CAS  PubMed  Google Scholar 

  87. Sofiadis A, Dinets A, Orre LM, et al. Proteomic study of thyroid tumors reveals frequent up-regulation of the Ca2+ -binding protein S100A6 in papillary thyroid carcinoma. Thyroid. 2010;20(10):1067–76.

    CAS  PubMed  Google Scholar 

  88. Hancq S, Salmon I, Brotchi J, et al. Detection of S100B, S100A6 and galectin-3 ligands in meningiomas as markers of aggressiveness. Int J Oncol. 2004;25(5):1233–40.

    CAS  PubMed  Google Scholar 

  89. Idriss MH, Elston DM. S100A6 expression in cutaneous smooth muscle neoplasms. APMIS. 2015;123(10):832–6.

    CAS  PubMed  Google Scholar 

  90. Kim J, Kim J, Yoon S, et al. S100A6 protein as a marker for differential diagnosis of cholangiocarcinoma from hepatocellular carcinoma. Hepatol Res. 2002;23(4):274.

    PubMed  Google Scholar 

  91. He X, Xu X, Khan AQ, Ling W. High expression of S100A6 predicts unfavorable prognosis of lung squamous cell cancer. Med Sci Monit. 2017;23:5011–7.

    PubMed  PubMed Central  Google Scholar 

  92. Ishii A, Suzuki M, Satomi K, et al. Increased cytoplasmic S100A6 expression is associated with pulmonary adenocarcinoma progression. Pathol Int. 2009;59(9):623–30.

    CAS  PubMed  Google Scholar 

  93. Ito Y, Yoshida H, Tomoda C, et al. Expression of S100A2 and S100A6 in thyroid carcinomas. Histopathology. 2005;46(5):569–75.

    CAS  PubMed  Google Scholar 

  94. Loosen SH, Benz F, Niedeggen J, et al. Serum levels of S100A6 are unaltered in patients with resectable cholangiocarcinoma. Clin Transl Med. 2016;5(1):39.

    PubMed  PubMed Central  Google Scholar 

  95. Zheng S, Shen H, Jia Q, et al. S100A6 promotes proliferation of intrahepatic cholangiocarcinoma cells via the activation of the p38/MAPK pathway. Future Oncol. 2017;13(23):2053–63.

    CAS  PubMed  Google Scholar 

  96. Nipp M, Elsner M, Balluff B, et al. S100–A10, thioredoxin, and S100–A6 as biomarkers of papillary thyroid carcinoma with lymph node metastasis identified by MALDI imaging. J Mol Med (Berl). 2012;90(2):163–74.

    CAS  PubMed  Google Scholar 

  97. Ohuchida K, Mizumoto K, Yu J, et al. S100A6 is increased in a stepwise manner during pancreatic carcinogenesis: clinical value of expression analysis in 98 pancreatic juice samples. Cancer Epidemiol Biomarkers Prev. 2007;16(4):649–54.

    CAS  PubMed  Google Scholar 

  98. Ohuchida K, Mizumoto K, Ishikawa N, et al. The role of S100A6 in pancreatic cancer development and its clinical implication as a diagnostic marker and therapeutic target. Clin Cancer Res. 2005;11(21):7785–93.

    CAS  PubMed  Google Scholar 

  99. Nishi M, Matsumoto K, Kobayashi M, et al. Serum expression of S100A6 is a potential detection marker in patients with urothelial carcinoma in the urinary bladder. Biomed Res. 2014;35(6):351–6.

    CAS  PubMed  Google Scholar 

  100. Onsurathum S, Haonon O, Pinlaor P, et al. Proteomics detection of S100A6 in tumor tissue interstitial fluid and evaluation of its potential as a biomarker of cholangiocarcinoma. Tumour Biol. 2018;40(4):1010428318767195.

    PubMed  Google Scholar 

  101. Zhang J, Zhang K, Jiang X, Zhang J. S100A6 as a potential serum prognostic biomarker and therapeutic target in gastric cancer. Dig Dis Sci. 2014;59(9):2136–44.

    CAS  PubMed  Google Scholar 

  102. Yang YQ, Zhang LJ, Dong H, et al. Upregulated expression of S100A6 in human gastric cancer. J Dig Dis. 2007;8(4):186–93.

    CAS  PubMed  Google Scholar 

  103. Wang T, Liang Y, Thakur A, et al. Diagnostic significance of S100A2 and S100A6 levels in sera of patients with non-small cell lung cancer. Tumour Biol. 2016;37(2):2299–304.

    CAS  PubMed  Google Scholar 

  104. Wei BR, Hoover SB, Ross MM, et al. Serum S100A6 concentration predicts peritoneal tumor burden in mice with epithelial ovarian cancer and is associated with advanced stage in patients. PLoS One. 2009;4(10):e7670.

    PubMed  PubMed Central  Google Scholar 

  105. Rehman I, Cross SS, Azzouzi AR, et al. S100A6 (Calcyclin) is a prostate basal cell marker absent in prostate cancer and its precursors. Br J Cancer. 2004;91(4):739–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Blanpain C, Fuchs E. Epidermal stem cells of the skin. Annu Rev Cell Dev Biol. 2006;22:339–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Ito M, Kizawa K. Expression of calcium-binding S100 proteins A4 and A6 in regions of the epithelial sac associated with the onset of hair follicle regeneration. J Invest Dermatol. 2001;116(6):956–63.

    CAS  PubMed  Google Scholar 

  108. Tumbar T, Guasch G, Greco V, et al. Defining the epithelial stem cell niche in skin. Science. 2004;303(5656):359–63.

    CAS  PubMed  Google Scholar 

  109. Ouji Y, Yoshikawa M, Nishiofuku M, Ouji-Sageshima N, Kubo A, Ishizaka S. Effects of Wnt-10b on proliferation and differentiation of adult murine skin-derived CD34 and CD49f double-positive cells. J Biosci Bioeng. 2010;110(2):217–22.

    CAS  PubMed  Google Scholar 

  110. Joost S, Zeisel A, Jacob T, et al. Single-cell transcriptomics reveals that differentiation and spatial signatures shape epidermal and hair follicle heterogeneity. Cell Syst. 2016;3(3):221-237.e229.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Chovatiya G, Ghuwalewala S, Walter LD, Cosgrove BD, Tumbar T. High-resolution single-cell transcriptomics reveals heterogeneity of self-renewing hair follicle stem cells. Exp Dermatol. 2021;30(4):457–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.

    CAS  PubMed  Google Scholar 

  113. Jia Z, Wang S, Liu Q. Identification of differentially expressed genes by single-cell transcriptional profiling of umbilical cord and synovial fluid mesenchymal stem cells. J Cell Mol Med. 2020;24(2):1945–57.

    CAS  PubMed  Google Scholar 

  114. Yamada J, Jinno S. S100A6 (calcyclin) is a novel marker of neural stem cells and astrocyte precursors in the subgranular zone of the adult mouse hippocampus. Hippocampus. 2014;24(1):89–101.

    CAS  PubMed  Google Scholar 

  115. Bartkowska K, Swiatek I, Aniszewska A, et al. Stress-dependent changes in the CacyBP/SIP interacting protein S100A6 in the mouse brain. PLoS One. 2017;12(1):e0169760.

    PubMed  PubMed Central  Google Scholar 

  116. Kjell J, Fischer-Sternjak J, Thompson AJ, et al. Defining the adult neural stem cell niche proteome identifies key regulators of adult neurogenesis. Cell Stem Cell. 2020;26(2):277-293.e278.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Li N, Nakauka-Ddamba A, Tobias J, Jensen ST, Lengner CJ. Mouse label-retaining cells are molecularly and functionally distinct from reserve intestinal stem cells. Gastroenterology. 2016;151(2):298-310.e297.

    CAS  PubMed  Google Scholar 

  118. Sato T, Sase M, Ishikawa S, et al. Characterization of radioresistant epithelial stem cell heterogeneity in the damaged mouse intestine. Sci Rep. 2020;10(1):8308.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea–a paradigm shift. Cancer Res. 2006;66(4):1883–90 discussion 1895-1886.

    CAS  PubMed  Google Scholar 

  120. Harris MA, Yang H, Low BE, et al. Cancer stem cells are enriched in the side population cells in a mouse model of glioma. Cancer Res. 2008;68(24):10051–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kanojia D, Zhou W, Zhang J, et al. Proteomic profiling of cancer stem cells derived from primary tumors of HER2/Neu transgenic mice. Proteomics. 2012;12(22):3407–15.

    CAS  PubMed  Google Scholar 

  122. Doulatov S, Notta F, Laurenti E, Dick JE. Hematopoiesis: a human perspective. Cell Stem Cell. 2012;10(2):120–36.

    CAS  PubMed  Google Scholar 

  123. Grahn THM, Niroula A, Végvári Á, et al. S100A6 is a critical regulator of hematopoietic stem cells. Leukemia. 2020;34(12):3323–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Balanescu P, Balanescu E, Baicus C, Balanescu A. S100A6, calumenin and cytohesin 2 as biomarkers for cutaneous involvement in systemic sclerosis patients: a case control study. J Pers Med. 2021;11(5):368.

    PubMed  PubMed Central  Google Scholar 

  125. Landi C, Bargagli E, Carleo A, et al. Bronchoalveolar lavage proteomic analysis in pulmonary fibrosis associated with systemic sclerosis: S100A6 and 14-3-3ε as potential biomarkers. Rheumatology (Oxford). 2019;58(1):165–78.

    CAS  PubMed  Google Scholar 

  126. Hoyaux D, Alao J, Fuchs J, et al. S100A6, a calcium- and zinc-binding protein, is overexpressed in SOD1 mutant mice, a model for amyotrophic lateral sclerosis. Biochim Biophys Acta. 2000;1498(2–3):264–72.

    CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 82272536), Gansu Youth Science and Technology Fund Program, China (No. 21JR11RA198).

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Authors and Affiliations

  1. Department of Joint Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shanxi, China

    Yidian Wang & Xin Kang

  2. Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou, China

    Xuewen Kang & Fengguang Yang

  3. The Second Clinical Medical College, Lanzhou University, Lanzhou, China

    Xuewen Kang & Fengguang Yang

  4. Orthopaedics Key Laboratory of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China

    Xuewen Kang & Fengguang Yang

  5. The Orthopedics Department of the Second Hospital of Lanzhou University, 82 Cuiying Men, Lanzhou, Gansu Province, 730000, PR China

    Fengguang Yang

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  1. Yidian Wang
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  3. Xin Kang
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Xin Kang and Fengguang Yang conceptualized the study. Yidian Wang and Xuewen Kang wrote the manuscript. All the authors contributed to manuscript editing and revision.

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Wang, Y., Kang, X., Kang, X. et al. S100A6: molecular function and biomarker role. Biomark Res 11, 78 (2023). https://doi.org/10.1186/s40364-023-00515-3

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Keywords

Biomarker Research

ISSN: 2050-7771

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