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

Changjun He,Deli Dong,Baoxin Li,Shidong Xu,Hongchi Jiang,Xueying Sun,Xian Jiang,Xuesong Dong,Bo Zhai

doi:10.18632/oncotarget.4814

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.

Highlights

Hepatocellular carcinoma (HCC) is the second leading cause of worldwide cancer-related death in men [1]
Inhibition of autophagy contributes to sorafenib resistance in HCC cells Given that mammalian target of rapamycin (mTOR) is a gatekeeper of autophagy by dysregulating autophagy-related protein (ATG) [37], we investigated whether inhibition of autophagy contributes to the acquired resistance to sorafenib
Given that miR-21 regulates phosphatase and tensin homolog (PTEN) expression and sequential Akt activation, which contribute to the sorafenib resistance in HCC cells, we examined whether miR-21 could influence the effects of sorafenib on the viability and apoptosis of HCC cells

Summary

Introduction

Hepatocellular carcinoma (HCC) is the second leading cause of worldwide cancer-related death in men [1]. Sorafenib is a first-line systemic drug for advanced HCC, but has only limited survival benefits [3, 4]. It is, important to unravel the molecular mechanisms that underlie sorafenib resistance in HCC. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway cross-talks with the Raf/MAPK/ERK pathway [5], and represents a key signaling pathway activated in hepatocarcinogenesis [6, 7]. Blockade of the PI3K/Akt pathway increases the sensitivity of sorafenib against HCC [9, 11, 12]. We have recently demonstrated that sorafenib-resistant HCC cells had increased expression of phosphorylated Akt (p-Akt), www.impactjournals.com/oncotarget and inhibition of Akt reversed the acquired resistance to sorafenib [13]. The mechanisms by which sorafenib activates Akt in HCC remain unclear

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