MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway

Abstract

// Changjun He 1, 2, 3 , Xuesong Dong 3 , Bo Zhai 3 , Xian Jiang 3 , Deli Dong 2 , Baoxin Li 2 , Hongchi Jiang 3 , Shidong Xu 1 , Xueying Sun 3 1 Department of Surgery, the Affiliated Cancer Hospital of Harbin Medical University, Harbin, China 2 Department of Pharmacology, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, China 3 The Hepatosplenic Surgery Center, Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China Correspondence to: Xueying Sun, e-mail: kevsun88@hotmail.com , k.sun@auckland.ac.nz Shidong Xu, e-mail: xusd163@163.com Keywords: sorafenib, hepatocellular carcinoma, miR-21, phosphatase and tensin homolog, Akt, autophagy Received: March 23, 2015 Accepted: July 17, 2015 Published: July 30, 2015 ABSTRACT Sorafenib resistance remains a major obstacle for the effective treatments of hepatocellular carcinoma (HCC). Recent studies indicate that activated Akt contributes to the acquired resistance to sorafenib, and miR-21 dysregulates phosphatase and tensin homolog (PTEN), which inhibits Akt activation. Sorafenib-resistant HCC cells were shown to be refractory to sorafenib-induced growth inhibition and apoptosis. Akt and its downstream factors were highly activated and/or upregulated in sorafenib-resistant cells. Inhibition of autophagy decreased the sensitivity of sorafenib-resistant cells to sorafenib, while its induction had the opposite effect. Differential screening of miRNAs showed higher levels of miR-21 in sorafenib-resistant HCC cells. Exposure of HCC cells to sorafenib led to an increase in miR-21 expression, a decrease in PTEN expression and sequential Akt activation. Transfection of miR-21 mimics in HCC cells restored sorafenib resistance by inhibiting autophagy. Anti-miR-21 oligonucleotides re-sensitized sorafenib-resistant cells by promoting autophagy. Inhibition of miR-21 enhances the efficacy of sorafenib in treating sorafenib-resistant HCC tumors in vivo . We conclude that miR-21 participates in the acquired resistance of sorafenib by suppresing autophagy through the Akt/PTEN pathway. MiR-21 could serve as a therapeutic target for overcoming sorafenib resistance in the treatment of HCC.