Hydroxychloroquine (Hcq) modulates autophagy and oxidative dna damage stress in hepatocellular carcinoma to overcome sorafenib resistance via tlr9/sod1/hsa-mir-30a5p/beclin-1 axis

Ming Yao Chen, Vijesh Kumar Yadav, Yi Cheng Chu, Jiann Ruey Ong, Ting Yi Huang, Kwai Fong Lee, Kuen Haur Lee, Chi Tai Yeh, Wei Hwa Lee

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Sorafenib is used for treating advanced hepatocellular carcinoma (HCC), but some patients acquire sorafenib resistance. We investigated the mechanisms underlying acquired sorafenib resistance in HCC cells and targeted them to re-sensitize them to sorafenib. In silico analysis indicated that toll-like receptor (TLR)-9 was significantly overexpressed, and that miRNA (hsa-miR30a-5p) was downregulated in sorafenib-resistant HCC cells, which modulated HCC cell proliferation, oxidative stress, and apoptosis. TLR9 overexpression increased HCC cell proliferation, whereas TLR9 inhibition from hydroxychloroquine (HCQ) decreased HCC cell proliferation, tumor growth, oxidative stress marker (SOD1), and the formation of autophagosome bodies (reduced ATG5 and Beclin-1 expression). Moreover, HCQ treatment reduced epithelial–mesenchymal transition, leading to decreased clonogenicity, migratory ability, and invasiveness. HCQ targeted and reduced the self-renewal capacity phenotype by inhibiting tumorsphere generation. Both in vitro and in vivo results demonstrated the synergistic effect of the HCQ–sorafenib combination on sorafenibresistant HCC (Huh7-SR) cells, increasing their sensitivity to treatment by modulating TLR9, autophagy (ATG5 and Beclin-1), oxidative stress (SOD1), and apoptosis (c-caspase3) expression and thus overcoming the drug resistance. This study’s findings indicate that TLR9 overexpression occurs in sorafenib-resistant HCC cells and that its downregulation aids HCC suppression. Moreover, HCQ treatment significantly increases sorafenib’s effect on sorafenib-resistant HCC cells.

Original languageEnglish
Article number3227
JournalCancers
Volume13
Issue number13
DOIs
Publication statusPublished - Jul 1 2021

Keywords

  • Autophagy
  • HCQ
  • Hepatocellular carcinoma
  • Oxidative stress
  • Sorafenib resistance
  • TLR9

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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