A miR-7/GAS6/TYRO3 axis regulates the growth and invasiveness of sorafenib-resistant cells in human hepatocellular carcinoma

Abstract

Sorafenib remains the only approved drug for treating patients with advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is transient and patients invariably develop sorafenib resistance (SR). Recently, TYRO3, a member of the TAM family of receptor tyrosine kinases, was identified as being aberrantly expressed in a significant proportion of HCC, however its role in SR is unknown. In this study, we generated two functionally distinct sorafenib resistant human Huh-7 HCC cell lines, in order to identify new mechanisms to abrogate acquired SR, as well as new potential therapeutic targets in HCC. Initially, we investigated the effects of a microRNA, miR-7, in both in vitro and in vivo preclinical models of human HCC and identified miR-7 as a potent tumour suppressor of human HCC. We identified TYRO3 as a new functional target of miR-7, which regulates proliferation, migration and invasion of Huh-7 cells via the PI3-Kinase/AKT pathway and is markedly elevated upon acquisition of SR. Furthermore, miR-7 effectively silenced TYRO3 expression in both sorafenib-sensitive and sorafenib-resistant Huh-7 cells inhibiting TYRO3/GAS6 mediated cancer cell migration and invasion. In conclusion, we identified a novel mechanism for acquiring SR in HCC which is via the aberrant expression of the TYRO3/PI3-Kinase/AKT signal transduction pathway, a mechanism that can be overcome by miR-7 over-expression. Taken together, these data suggest a potential role for miR-7 as an RNA-based therapeutic to treat refractory and drug resistant HCC. This article is protected by copyright. All rights reserved.

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