PERK/ATF4-Dependent ZFAS1 Upregulation Is Associated with Sorafenib Resistance in Hepatocellular Carcinoma Cells.

Jiunn-Chang Lin,Pei-Ming Yang,Tsang-Pai Liu

doi:10.3390/ijms22115848

Abstract

Sorafenib, a multi-kinase inhibitor, is the first-line treatment for advanced hepatocellular carcinoma (HCC) patients. However, this drug only provides a short improvement of patients’ overall survival, and drug resistance is commonly developed. Thus, the identification of resistant factor(s) or biomarker(s) is needed to develop more efficient therapeutic strategies. Long, non-coding RNAs (lncRNAs) have recently been viewed as attractive cancer biomarkers and drive many important cancer phenotypes. A lncRNA, ZFAS1 (ZNFX1 antisense RNA 1) has been found to promote HCC metastasis. This study found that sorafenib induced ZFAS1 expression specifically in sorafenib-resistant HCC cells. Although ZFAS1 knockdown did not restore the sensitivity of HCC cells to sorafenib, its expression may act as a resistant biomarker for sorafenib therapy. Bioinformatics analysis predicted that sorafenib tended to induce pathways related to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in sorafenib-resistant HCC cells. In vitro experimental evidence suggested that sorafenib induced protein kinase RNA-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-dependent ZFAS1 expression, and sorafenib resistance could be overcome by PERK/ATF inhibitors. Therefore, PERK/ATF4/ZFAS1 signaling axis might be an attractive therapeutic and prognostic biomarker for sorafenib therapy in HCC.

Highlights

Multi-kinase inhibitors have been approved for treating hepatocellular carcinoma (HCC) in recent years, including sorafenib, regorafenib, lenvatinib, and cabozantinib [1,2,3,4]
It has been reported that HepG2 is a sorafenib-sensitive HCC cell line, whereas PLC5 cells are a sorafenib-resistant HCC cell line [20]
Our results showed the resistance of PLC5 cells to sorafenib (Figure 1A), which will be used as a cell model for primary sorafenib resistance

Summary

Introduction

Multi-kinase inhibitors have been approved for treating hepatocellular carcinoma (HCC) in recent years, including sorafenib, regorafenib, lenvatinib, and cabozantinib [1,2,3,4] They only provide a short improvement of HCC patients’ overall survival [1,2,3,4]. A recent review article summarizes the potential resistant factors, including activation of EGFR (epidermal growth factor receptor), AKT and c-Jun oncogenic signaling pathways, autophagy, epithelial–mesenchymal transition (EMT), hypoxia, cancer stemness, dysregulation of the cell cycle, and apoptosis resistance. Drugs targeting these resistant factors might be able to improve the sorafenib efficacy or treat sorafenib-refractory HCC patients [7]

Methods

Results

Conclusion