- Open Access
Advance in microRNA as a potential biomarker for early detection of pancreatic cancer
Biomarker Research volume 4, Article number: 20 (2016)
Pancreatic cancer is characterized as a disease with low survival and high mortality because of no effective diagnostic and therapeutic strategies available in clinic. Conventional clinical diagnostic methods including serum markers and radiological imaging (CT, MRI, EUS, etc.) often fail to detect precancerous or early stage lesions. Development of effective biomarkers is unmet for reduction of mortality of pancreatic cancer. MicroRNAs (miRNAs) are a group of small non-protein-coding RNAs playing roles in regulation of cell physiology including tumorigenesis, apoptotic escape, proliferation, invasion, epithelial-mesenchymal transition (EMT), metastasis and chemoresistance. Various altered signaling pathways involving in molecular pathogenesis of pancreatic cancer are mediated by miRNAs as a role of either oncogenes or tumor suppressors. Among biomarkers developed including protein, metabolites, DNA, RNA, epigenetic mutation, miRNAs are superior because of its unique chemical property. Recent study suggests that miRNAs may be promising biomarkers used for early detection of pancreatic cancer. This review will update the progression made in early detection of pancreatic cancer.
Pancreatic cancer has an exceptionally low 5-year survival rate (<5 %) and high mortality rate, making it the fourth leading cause of cancer mortality in developed countries . As it is particularly located in an inaccessible position of the abdomen leading the common clinical presentation, greater than 80 % of the affected patients were diagnosed when occurring locally advancing or metastasis . Thus the early diagnosis of pancreatic cancer is the key for successful treatment of the disease, though it is rendered uneasy to accomplish resulted from the deficiency of early warning signs. Although much more research into biomarkers has been investigated, few biomarkers are proven to be effective used for early diagnosis of the disease . Therefore, seeking novel biomarkers with higher sensitivity or specificity is still a challenge.
miRNAs are small non-protein-coding RNAs consisting of 18–24 nucleotides in length involving in regulating multiple gene expression by degrading target mRNAs or inhibiting translation at the post-transcriptional level, thereby regulating various neoplastic processes including cell proliferation, migration, invasion, survival, and metastasis . Disregulation of miRNA plays an important role in the pathogenesis, diagnosis and therapy of pancreatic cancer . Here, we update progression made in miRNA as early diagnostic/prognostic biomarkers for pancreatic cancer.
Cancer diagnosis by imaging and biomarkers
Imaging technology has been widely applied as routine methods in diagnosis, therapy and prognosis of varied tumor types including pancreatic cancer. Although common imaging modalities consisting of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreatography (ERCP) have been remarkably improved in their detection of pancreatic tumor as by positron emission tomography (PET) or their combination, sensitivity and specificity of detection of pancreatic cancer at its early stage remains challenge [5, 6].
As for CA 19-9, widely used biomarker, fails to distinguish pancreatic cancer from benign pancreatic diseases and multiple carcinoma, which limits clinical utility because of its inadequate sensitivity and specificity . Similarly, several other serum and tissue-based biomarkers (Table 1) suffering the same limitation as CA 19-9, thus none of them have good clinical utility for early diagnosis of pancreatic cancer . Effective biomarkers thus coupled with imaging would provide an ideal approach for early detection of cancer .
MicroRNAs as effective biomarkers
Currently, a large sum of studies have identified the potential role of miRNAs in tumorigenesis and metastasis, suggesting that it may be developed as biomarkers used for diagnosis, prognosis and prediction of pancreatic cancer . Given that miRNA-mediated transcriptional regulation is involved in every cellular process, abnormal alterations in miRNA expression are commonly associated with all the carcinogenic process of pancreatic ductal adenocarcinoma (PDAC), including apoptosis escape, proliferation, invasion, epithelial-mesenchymal transition (EMT), metastasis and chemoresistance [8, 9]. Based on their expression, a handful of miRNAs up-regulated in tumor cells are classified as potent oncogenes, while some others are classified as tumor suppressors since they are conversely down-regulated during the tumorigenesis . MiR-21, for instance, is classified as an oncogene because whose over-expression is associated with the increased proliferation, invasion, and chemoresistance of pancreatic cancer cells to Gemcitabine. Like miR-21, several other miRNAs, which clearly presented their over-expression in cancer tissues, include miR-155, miR-106a, miR-27a, miR-221/222, miR-224, miR-486, miR-194, miR-200b/c, miR-429, miR-10a/b, miR-367, miR-196a/b, miR-210, miR-375, and miR-301a [9, 10]. Meanwhile, another group of miRNAs showed inhibitory effects on cell proliferation, invasion and metastasis, thus functioned as tumor suppressors, including miR-34a/b, Let-7, miR-96, miR-124, miR-615-5p, miR-200a/b/c, miR-219-1-3p, miR-203, miR-146a, and miR-17-92 [9, 10]. An interesting study showed that miR-17-92 cluster is down-regulated in pancreatic cancer stem cells (CSCs), which showed highly resistant to chemotherapy by activating NODAL/ACTIVIN/TGF-β1 signaling pathways, thus, suppression of these pathways may enhance the sensitivity of pancreatic CSCs to chemotherapy .
miRNAs regulate key biological processes of tumor cells by altering signaling pathways involved in molecular pathogenesis of PDAC, including K-ras, p53, SMAD4, E-cad, PTEN, ADAM9, Bcl-2, STAT3, Cyclin D1, EGFR, TGF-β, JNK, Hedgehog, Notch, NF-κB, and Akt-2 . RAS associated signaling pathways are derived from the most frequently mutated KRAS in 90 % of pancreatic cancer, whose translation was found to be mediated by miR-96, miR-126, miR-143/145, miR-217 and Let-7 . Recently p53 has been shown to mediate regulation of miR-34 family (miR-34a/b/c). miRNAs such as miR-21, miR-143, miR-155, miR-130a/301a/454, miR-224, miR-146a, miR-483-3p, miR-494, miR-494, and miR-421 are involved in pancreatic cancer progression by regulating TGF-β/SMAD-4 signaling either directly or indirectly . Moreover, miR-137 targets KDM4A mRNA during Ras-induced senescence, and activates both p53 and retinoblastoma (pRb) . More information about miRNAs as biomarkers and their targeting pathways are summarized in Fig. 1.
As aberrant expression of miRNA occurs in molecular pathogenesis of pancreatic cancer, identification of miRNA signatures differentially expressed in different pathological stages of the disease may distinguish pancreatic cancer from pancreatic benign diseases with excellent sensitivity or specificity. A recent study in serum from patients with pancreatic cancer demonstrated that seven serum miRNAs, including miR-20a, miR-21, miR-24, miR-25, miR-99a, miR-185, miR-191, differentially expressed in pancreatic cancer compared to cancer-free subjects, suggesting this miRNA profile may be developed as an effective biomarker used for early detection of the disease with high sensitivity and specificity . More study identified a panel of five miRNAs including miR-10b, −155, −106b, −30c, and −212 in plasma and bile had excellent accuracy, sensitivity, and specificity for detection of PDAC over the control(patients with choledocholithiasis but normal pancreata) . Similarly, miR-21, miR-210, miR-155, and miR-196a showed significant difference in cancer versus healthy control, further study on miR-21 suggests that this miRNA can be developed as an independent prognostic biomarker distinguishing invasive from non-invasive macroscopic intraductal papillary mucinous neoplasms (IPMN), which is one of the precursor lesions of PDAC [15, 16]. It is worth noting that miRNA biomarkers can play a supplementary role with several protein markers in early identification of pancreatic cancer. The combination of a panel of miRNAs, especially miR-16 and miR-196a with CA19-9, for instance, showed effective at identification of tumors in Stage 1 . Pancreatic cancer -initiating cell (PaCIC) markers, such as CD44v6, Tspan8, EpCAM, MET and CD104, combined with miRNA serum-exosome biomarkers including miR-1246, miR-4644, miR-3976 and miR-4306, improved sensitivity significantly with a specificity of 80 % for pancreatic cancer compared to all others groups . Table 2 lists the sensitivity and the specificity of the miRNAs mentioned above.
Although more data suggest that miRNAs offers great potential as biomarkers for early detection of pancreatic cancer, there are limited prospective validation studies to prove their efficacy. Most studies thus far have been in the case-control stage, its application in clinic for prediction and diagnosis of pancreatic cancer at its early stages remained challenge. This may be due to lack of effective standard operational procedures (SOPs) used in standardized clinical assays. Secondarily, no consensus is agreed about the mechanisms underlying miRNA deregulation in tumor cells, hence understanding better the role of miRNAs in tumorigensis may eradicate the field of both molecular diagnosis and effective therapy of pancreatic cancer.
As gene regulators, miRNAs can regulate cell growth, differentiation and apoptosis in many cases of human tumor. Abnormal expression of miRNAs in pancreatic cancer is the early events of pancreatic cancer development, which makes it can be used as a new biological marker for early detection of pancreatic cancer. Evaluation of single miRNA plays an important role in biomarker research, however, a single biomarker is often limitaed in sensitivity and specificity. A miRNA profile consists of a panel of up-regulated or down-regulated miRNAs, thus it can reflect the tumor progression with high sensitivity and specificity. Although there have been a large number of literatures which stated the potetial role of miRNAs as biomarker in pancreatic cnacer early detection, the application in clinical is still remains to explore.
Cancer stem cells
Endoscopic retrograde cholangiopancreatography
Endoscopic ultrasound-Fine needle aspiration
Intraductal papillary mucinous neoplasms
Magnetic resonance imaging
Pancreatic cancer-initiating cell
Pancreatic ductal adenocarcinoma
Positron emission tomography
p53 and retinoblastoma
Standard operational procedures
Li A, Yu J, Kim H, Wolfgang CL, Canto MI, Hruban RH, et al. MicroRNA array analysis finds elevated serum mir-1290 accurately distinguishes patients with low-stage pancreatic cancer from healthy and disease controls. Clin Cancer Res. 2013;19(13):3600–10.
Chitkara D, Mittal A, Mahato RI. miRNAs in pancreatic cancer: therapeutic potential, delivery challenges and strategies. Adv Drug Deliv Rev. 2015;81:34–52.
Rachagani S, Macha MA, Heimann N, Seshacharyulu P, Haridas D, Chugh S, et al. Clinical implications of miRNAs in the pathogenesis, diagnosis and therapy of pancreatic cancer. Adv Drug Deliv Rev. 2015;81:16–33.
Munding JB, Adai AT, Maghnouj A, Urbanik A, Zöllner H, Liffers ST, et al. Global microRNA expression profiling of microdissected tissues identifies miR-135b as a novel biomarker for pancreatic ductal adenocarcinoma. Int J Cancer. 2012;131(2):E86–95.
Oberg K, Modlin IM, Herder WD, Pavel M, Klimstra D. Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol. 2015;16:e435–46.
Miura F, Takada T, Amano H, Yoshida M, Furui S, Takeshita K. Diagnosis of pancreatic cancer. HPB. 2006;8(5):337–42.
Duffy MJ, Sturgeon C, Lamerz R, Haglund C, Holubec VL, Klapdor R, et al. Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. Ann Oncol. 2010;21(3):441–7.
Karius T, Schnekenburger M, Dicato M, Diederich M. MicroRNAs in cancer management and their modulation by dietary agents. Biochem Pharmacol. 2012;83(12):1591–601.
Brunetti O, Russo A, Scarpa A, Santini D, Reni M, Bittoni A, et al. MicroRNA in pancreatic adenocarcinoma: predictive/prognostic biomarkers or therapeutic targets? Oncotarget. 2015;6(27):23323–41.
Khan S, Ansarullah DK, Jaggi M, Chauhan SC. Targeting microRNAs in pancreatic cancer: microplayers in the big game. Cancer Res. 2013;73(22):6541–7.
Cioffi M, Trabulo SM, Sanchez-Ripoll Y, Miranda-Lorenzo I, Lonardo E, Dorado J, et al. The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells. Gut. 2015;64(12):1936–48.
Neault M, Mallette FA, Richard S. miR-137 modulates a tumor suppressor network-inducing senescence in pancreatic cancer cells. Cell Rep. 2016;14(8):1966–78.
Liu R, Chen X, Du Y, Yao W, Shen L, Wang C, et al. Serum MicroRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer. Clin Chem. 2012;58(3):610–8.
Cote GA, Jesse Gore A, McElyea SD, Heathers LE, Xu H, Sherman S, et al. A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile. Am J Gastroenterol. 2014;109:1942–52.
Wang J, Chen J, Chang P, Leblanc A, Li D, Abbruzzesse JL, et al. MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prev Res. 2009;2(9):807–13.
Caponi S, Funel N, Frampton AE, Mosca F, Santarpia L, Van der Velde AG, et al. The good, the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms. Ann Oncol. 2013;24(3):734–41.
Liu J, Gao J, Du Y, Li Z, Ren Y, Gu J, et al. Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer. Int J Cancer. 2012;131(3):683–91.
Madhavan B, Yue S, Galli U, Rana S, Gross W, Müller M, et al. Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer. 2015;136(11):2616–27.
Schima W, Függer R, Schober E, Oettl C, Wamser P, Grabenwöger F, et al. Diagnosis and staging of pancreatic cancer: comparison of Mangafodipir Trisodium–enhanced MR imaging and contrast-enhanced helical hydro-CT. Am J Roentgenol. 2002;179:717–24.
Ryozawa S, Kitoh H, Gondo T, Urayama N, Yamashita H, Ozawa H, et al. Usefulness of endoscopic ultrasound-guided fine-needle aspiration biopsy for the diagnosis of pancreatic cancer. J Gastroenterol. 2005;40(9):907–11.
Diehl SJ, Lehmann KJ, Gaa J, Meier-Willersen HJ, Wendl K, Georgi M. Pancreatic cancer: value of MRI including MR cholangio-pancreatography (MRCP) compared to endoscopic retrograde cholangiopancreatography (ERCP). ROFO-FORTSCHRITTE AUF DEM GEBIET DER RONTGENSTRAHLEN UND DER BILDGEBENDEN VERFAHREN. 1999;170(5):463–9.
Sun Y, Duan Q, Wang S, Yuecan Zeng WR. Diagnosis of pancreatic cancer using 18 F-FDG PET/CT and CA19-9 with SUVmax association to clinical characteristics. JBUON. 2015;20(2):452–9.
Luo G, Xiao Z, Long J, Liu Z, Liu L, Liu C, et al. CA125 is Superior to CA19-9 in predicting the resectability of pancreatic cancer. J Gastrointest Surg. 2013;17(12):2092–8.
Thank you to the DUT International Center for Metabolomics.
This work was supported by the DUT International Center for Metabolomics in the School of Pharmaceutical Science and Technology, Dalian University of Technology.
Availability of data and materials
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
About this article
Cite this article
Huang, J., Liu, J., Chen-Xiao, K. et al. Advance in microRNA as a potential biomarker for early detection of pancreatic cancer. Biomark Res 4, 20 (2016). https://doi.org/10.1186/s40364-016-0074-3
- Early detection
- Pancreatic cancer
- Cancer stem cells
- Signal transduction