CHARACTERIZATION OF MICRORNA DEREGULATION IN HEPATOCELLULAR CARCINOMA

Abstract

Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide with an annual global mortality of ~700,000. HCC is a very complex disease and the role of miRNAs in HCC is not fully understood. In this study, we profiled miRNA expression in tumor versus paired adjacent non-tumor tissues from 100 HCC patients and identified a miRNA signature of 66 significantly (FDR<0.000) differentially expressed miRNAs associated with HCC. We subsequently characterized let-7a down-regulation and miR- 224 up-regulation. We demonstrated that hepatitis B virus X protein (HBx) down-regulates let-7a and let-7a negatively regulates cell proliferation through targeting Signal Transduction and Activator of Transcription 3 (STAT3). The HBx-let-7-STAT3 pathway supports cell proliferation in HBx-expressing cells. Additionally, we demonstrated that over-expression of miR-224 increases cell proliferation by targeting SMAD family member 4 (SMAD4) and sensitizes cells to apoptotic cell death by targeting Apoptotis Inhibitor 5 (API5). We observed statistically significant (p<0.05) inverse correlation between let-7a & STAT3, miR-224 & SMAD4 and miR-224 & API5 in HCC patients, demonstrating the clinical relevance of our observation. Therefore, our work contributed to the identification of miRNA deregulation in HCC and the understanding of the functional relevance of two such miRNA deregulations with respect to HCC.