Underexpressed microRNA-199b-5p targets Hypoxia-Inducible Factor-1α in hepatocellular carcinoma and predicts prognosis of hepatocellular carcinoma patients

Background and Aim: MicroRNAs are short noncoding RNA molecules that are responsible for the posttranscriptional regulation of target genes. The aim of this study was to determine whether microRNA-199b-5p (miR-199b) plays a role in the progression and prognosis of hepatocellular carcinoma (HCC), and to elucidate whether hypoxia-inducible factor-1 alpha (Hif1 alpha) is regulated by miR-199b. Methods: In this study, 35 matched HCCs and cirrhosis tissues were assayed for miR-199b and Hif1a expression. To evaluate the role of miR-199b, we assessed cell proliferation rate and clonogenic survival of miR-199b- or negative control-transfected cells by MTT and clone formation assay, respectively. In addition, the regulation of Hif1 alpha by miR-199b was evaluated by Western blotting and luciferase assay. MiR-199b was down-regulated in 77% of HCCs, whereas Hif1 alpha protein was upregulated in 69% of cases. A significant inverse correlation between miR-199b and Hif1 alpha was observed in HCCs. Results: Patients with lower levels of miR-199b expression had poorer overall survival and progression-free survival rates, whereas patients with higher levels of miR-199b expression had better survival. Moreover, miR-199b could restrain cell growth and obviously enhance the radiosensitizing effect of HepG2 cells. MiR-199b and pGL3-Hif1 alpha vector-transfected cells showed suppressed Hif1 alpha protein expression and significant reduced luciferase activity. Conclusions: Underexpressed miR-199b, which may be via the upregulation of Hif1 alpha in HCCs, is inversely correlated with survival and directly correlated with the malignant status of HCC patients.