miR-181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF1 expression

Cancer Sci. 2016 Sep;107(9):1256-62. doi: 10.1111/cas.13006. Epub 2016 Sep 2.


Sorafenib, a multi-kinase inhibitor, is the only standard clinical drug for patients with advanced hepatocellular carcinoma (HCC); however, development of sorafenib resistance in HCC often prevents its long-term efficacy. Therefore, novel targets and strategies are urgently needed to improve the antitumor effect of sorafenib. In the present study, we examined the novel mechanisms of sorafenib resistance of HCC cells by investigating the difference in sorafenib sensitivity between two HCC cell lines. Sorafenib induced more apoptosis of HepG2 cells compared to Hep3B cells. Sorafenib exposure to HepG2 cells but not Hep3B cells increased the expression of proapoptotic factor PUMA, and activated PARP and caspase-3. Notably, microRNA-181a (miR-181a) expression levels were lower in HepG2 cells than in Hep3B cells. Exogenous miR-181a expression in HepG2 cells reduced apoptosis, whereas inhibition of miR-181a in Hpe3B cells increased apoptosis. In addition, we demonstrated that miR-181a directly targets RASSF1, a MAPK signaling factor, and knockdown of RASSF1 increased sorafenib resistance. Taken together, these results suggest that miR-181a provokes sorafenib resistance through suppression of RASSF1. Our data provide important insight into the novel therapeutic strategy against sorafenib resistance of HCC cells by targeting of miR-181a pathway.

Keywords: Apoptosis; RASSF1; hepatocellular carcinoma; miR-181a; sorafenib.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Carcinoma, Hepatocellular / genetics*
  • Caspase 3 / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / genetics*
  • MicroRNAs / genetics*
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Phenylurea Compounds / pharmacology
  • RNA Interference*
  • Sorafenib
  • Tumor Suppressor Proteins / genetics*


  • Antineoplastic Agents
  • MIRN-181 microRNA, human
  • MicroRNAs
  • Phenylurea Compounds
  • RASSF1 protein, human
  • Tumor Suppressor Proteins
  • Niacinamide
  • Sorafenib
  • Caspase 3