The Clinical Utility of MicroRNA as a Prognostic Biomarker of Pancreatobiliary Cancers

A microRNA (miRNA) is a small noncoding RNA molecule (containing about 22 nucleotides) found in plants, animals and some viruses that functions in RNA silencing and posttranscriptional regulation of gene expression. The miRNA induces gene silencing by binding to the 3′-untranslated regions (3′-UTRs) of target mRNAs. This interaction prevents protein production by inhibition of protein translation and/or by mRNA degradation. Therefore, miRNAs have been reported to have important functions in the regulation of carcinogenesis and cancer progression as well as homeostasis. This explains why miRNAs are intensely studied as candidates for diagnostic and prognostic biomarkers in cancers.

The miRNAs are invariably found to be misexpressed in every type of cancer examined so far, and miRNA genes can act as both tumor-suppressor genes and oncogenes. There were many studies about miRNA in pancreatobiliary cancers. Ali et al.¹ suggested that serum miR-21 and other miRNAs could predict the aggressiveness of pancreatic cancer. This miR-21 is overexpressed in cholangiocarcinoma and the knockdown of miR-21 resulted in inhibition of cellular invasion and metastasis.² As a result, miR-21 may be a potential biomarker for pancreatobiliary cancer prognosis. A combination of serum eight miRNAs (miR-6075, miR-4294, miR-6880-5p, miR-6799-5p, miR-125a-3p, miR-4530, miR-6836-3p, and miR-4476) suggested as early diagnostic biomarkers to detect pancreatobiliary cancers.³ The sensitivity, specificity, and accuracy to detect pancreatobiliary cancers showed superiority comparing to carbohydrate antigen 19-9 and carcinoembryonic antigen.

Pancreatobiliary cancers are highly malignant tumors and the overall prognosis is poor. This is why the new prognostic markers for pancreatobiliary cancers are very important and essential to treat and follow up on the aggressive cancers. In this issue of Gut and Liver, Kim et al.⁴ suggested that miRNA 141 may be a valuable prognostic biomarker in patients with biliary tract cancer. The miRNA 141 highly overexpressed in malignant cholangiocytes was suggested as an important regulator of tumor cell proliferation in vitro and decreasing miRNA 141 overexpression may be useful to inhibit tumor progress in previous study.⁵ Authors demonstrated that this miRNA 141 overexpression was related to poor disease-free survival in patients with biliary tract cancers. Moreover, they elucidated that miRNA 141 overexpression was significantly associated with angiolymphatic invasions by using surgical specimens. This study has an important clinical impact to clarify the function of miRNA 141 in carcinogenesis of biliary tract cancers. Nevertheless, there are several limitations in this study. Authors investigated only the tissue sample but not the serum sample. It is very important to know the result of serum sample since it increases clinical utility due to its easy sampling and continuous monitoring with the follow up. The number of patients which showed high expression of miRNA 141 was only 18%. Consequently, this alone cannot predict the poor prognosis of biliary tract cancers. Hence, for this reason other miRNAs or biomarkers should be combined to predict accurate prognosis. Recently, serum miR-26a was suggested as a potential prognostic biomarker in patients with cholangiocarcinoma.⁶

MicroRNAs have important roles in cancer by targeting corresponding mRNAs and by influencing hallmarks of cancer. This is related to cell proliferation, avoiding growth suppression, activating invasion and metastasis, angiogenesis, and resisting cell death. As a result, finding new prognostic biomarkers of microRNAs provide essential knowledge for prediction of patient prognosis and for discovery of new therapeutic targets for cancer treatment.