Advance in microRNA as a potential biomarker for early detection of pancreatic cancer
© The Author(s). 2016
Received: 1 September 2016
Accepted: 6 October 2016
Published: 22 October 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.
KeywordsEarly detection Pancreatic cancer Cancer stem cells microRNAs Signal transduction Biomarker
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].
Assay parameters of imaging modalities and classical biomarkers used in detection of pancreatic cancer
18F-FDGPE/CT + CA19-9
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 .
The AUC, sensitivity and specificity of miRNA-based biomarkers for detection of pancreatic cancer
PCa vs. Normal
PCa vs. CP
PCa vs. Normal
PCa vs. CP
PCa vs. Normal
PCa vs. CP
miR-20a, 21, 24, 25, 99a, 185, 191
miR-10b, 155, 106b, 30c, 212
miR-21, 210, 155, 196a
miR-1246, 4644, 3976, 4306
PaCIC marker + miR-1246, 4644, 3976, 4306
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
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
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