MiR-338-3p Inhibits Hepatocarcinoma Cells and Sensitizes These Cells to Sorafenib by Targeting Hypoxia-Induced Factor 1α

Hypoxia is a common feature of solid tumors and an important contributor to anti-tumor drug resistance. Hypoxia inducible factor-1 (HIF-1) is one of the key mediators of the hypoxia signaling pathway, and was recently proven to be required for sorafenib resistance in hepatocarcinoma (HCC). MicroRNAs have emerged as important posttranslational regulators in HCC. It was reported that miR-338-3p levels are associated with clinical aggressiveness of HCC. However, the roles of miR-338-3p in HCC disease and resistance to its therapeutic drugs are unknown. In this study, we found that miR-338-3p was frequently down-regulated in 14 HCC clinical samples and five cell lines. Overexpression of miR-338-3p inhibited HIF-1 alpha 3'-UTR luciferase activity and HIF-1 alpha protein levels in HepG2, SMMC-7721, and Huh7 cells. miR-338-3p significantly reduced cell viability and induced cell apoptosis of HCC cells. Additionally, HIF-1 alpha overexpression rescued and HIF-1a knock-down abrogated the anti-HCC activity of miR-338-3p. Furthermore, miR-338-p sensitized HCC cells to sorafenib in vitro and in a HCC subcutaneous nude mice tumor model by inhibiting HIF-1 alpha. Collectively, miR-338-3p inhibits HCC tumor growth and sensitizes HCC cells to sorafenib by down-regulating HIF-1 alpha. Our data indicate that miR-338-3p could be a potential candidate for HCC therapeutics.