Advance in microRNA as a potential biomarker for early detection of pancreatic cancer

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.


Background
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 [1]. 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 [2]. 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 [3]. 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 [4]. Disregulation of miRNA plays an important role in the pathogenesis, diagnosis and therapy of pancreatic cancer [3]. 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 [7]. 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 [7]. Effective biomarkers thus coupled with imaging would provide an ideal approach for early detection of cancer [5].
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 [13]. 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) [14]. 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 [17]. 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 [18]. Table 2 lists the sensitivity and the specificity of the miRNAs mentioned above.

Future perspective
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.

Conclusions
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.