Perk/atf4-dependent zfas1 upregulation is associated with sorafenib resistance in hepatocellular carcinoma cells

Jiunn Chang Lin, Pei Ming Yang, Tsang Pai Liu

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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 over-come by PERK/ATF inhibitors. Therefore, PERK/ATF4/ZFAS1 signaling axis might be an attractive therapeutic and prognostic biomarker for sorafenib therapy in HCC.

Original languageEnglish
Article number5848
JournalInternational journal of molecular sciences
Volume22
Issue number11
DOIs
Publication statusPublished - Jun 1 2021

Keywords

  • Drug resistance
  • ER stress
  • Hepatocellular carcinoma
  • Long non-coding RNA
  • Sorafenib
  • Unfolded protein response

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint

Dive into the research topics of 'Perk/atf4-dependent zfas1 upregulation is associated with sorafenib resistance in hepatocellular carcinoma cells'. Together they form a unique fingerprint.

Cite this