Research Paper Volume 12, Issue 18 pp 18192—18208

MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression

Zhong Wan1,2, *, , Tingyu Liu3, *, , Liang Wang1, , Rong Wang4, , Hai Zhang1, ,

  • 1 Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China
  • 2 Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
  • 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
  • 4 Department of Pharmacy, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201999, China
* Equal contribution

Received: September 27, 2019       Accepted: June 1, 2020       Published: September 21, 2020
How to Cite

Copyright: © 2020 Wan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


We investigated MAPK14-dependent resistance to sorafenib in hepatocellular carcinoma (HCC). Bioinformatics analysis and dual luciferase reporter assays in HCC cell lines showed that miR-216a-3p directly binds to the 3’UTR of MAPK14 mRNA and downregulates MAPK14 protein expression. Consequently, miR-216a-3p expression correlates inversely with MAPK14 protein levels in HCC patient tissues. miR-216a-3p overexpression significantly increases the sorafenib sensitivity of HCC cells by suppressing MAPK14 expression and reducing the subsequent activation of the MEK/ERK and ATF2 signaling pathways. The growth of xenograft tumors derived from miR-216a-3p-overexpression HCC cells was significantly diminished in sorafenib-treated Balb/c nude mice compared to controls. High miR-216a-3p levels in HCC tissue samples prior to treatment correlated with a better sorafenib response and favorable prognosis. Our findings thus demonstrate that miR-216a-3p enhances sorafenib sensitivity in HCC cells and tumor tissues by decreasing MAPK14 levels, thereby inhibiting the MAPK14-dependent MEK/ERK and ATF2 signaling.


MAPK14: mitogen-activated protein kinase; HCC: hepatocellular carcinoma; miRNA: micro RNA; ERK: extracellular regulated protein kinase; ATF2: activating transcription factor 2; RT-PCR: real-time PCR; WB: western blotting; DMEM: Dulbecco's modified Eagle's medium; IRS: immunoreactive score; IFA: Immuno-fluorescence assay; NC: normal control; DFS: Disease-free survival; ROC: receiver operating characteristic; IHC: Immunohistochemistry.