Activation of MET promotes resistance to sorafenib in hepatocellular carcinoma cells via the AKT/ERK1/2-EGR1 pathway

Qing Feng Xiang, Mei Xiao Zhan, Yong Li, Hui Liang, Cong Hu, Yao Ming Huang, Jing Xiao, Xu He, Yong Jie Xin, Min-Shan Chen, Li Gong Lu

Research output: Contribution to journalArticle

Abstract

Sorafenib is an oral multikinase inhibitor that has become an established therapeutic approach in advanced hepatocellular carcinoma (HCC). However, the benefit of sorafenib in clinical therapy is often affected by drug resistance. Therefore, it is important to explore the mechanisms underlying sorafenib resistance and to develop individualized therapeutic strategies for coping with this problem. In this study, we found that addition of HGF to sorafenib-treated HCC cells activated MET and re-stimulated the downstream AKT and ERK1/2 pathways. Thereby, restored sorafenib-treated HCC cells proliferation, migration and invasion ability, and rescued cells from apoptosis. In addition, we found that HGF treatment of HCC cells induced early growth response protein (EGR1) expression, which is involved in sorafenib resistance. Importantly, the HGF rescued effect in sorafenib-treated HCC cells could be abrogated by inhibiting MET activation with PHA-665752 or by downregulating EGR1 expression with small interfering RNA (siRNA). Therefore, inhibition of the HGF/MET pathway may improve response to sorafenib in HCC, and combination therapy should be further investigated.

Original languageEnglish (US)
Pages (from-to)83-89
Number of pages7
JournalArtificial cells, nanomedicine, and biotechnology
Volume47
Issue number1
DOIs
StatePublished - Dec 1 2019

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MAP Kinase Signaling System
Cell proliferation
Cell death
RNA
Hepatocellular Carcinoma
Chemical activation
Cells
Proteins
sorafenib
Therapeutics
Drug Resistance
Small Interfering RNA
Cell Movement
Down-Regulation
Cell Proliferation
Apoptosis
Growth

Keywords

  • hepatocellular carcinoma
  • MET
  • resistance
  • Sorafenib

ASJC Scopus subject areas

  • Biotechnology
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Pharmaceutical Science

Cite this

Activation of MET promotes resistance to sorafenib in hepatocellular carcinoma cells via the AKT/ERK1/2-EGR1 pathway. / Xiang, Qing Feng; Zhan, Mei Xiao; Li, Yong; Liang, Hui; Hu, Cong; Huang, Yao Ming; Xiao, Jing; He, Xu; Xin, Yong Jie; Chen, Min-Shan; Lu, Li Gong.

In: Artificial cells, nanomedicine, and biotechnology, Vol. 47, No. 1, 01.12.2019, p. 83-89.

Research output: Contribution to journalArticle

Xiang, Qing Feng ; Zhan, Mei Xiao ; Li, Yong ; Liang, Hui ; Hu, Cong ; Huang, Yao Ming ; Xiao, Jing ; He, Xu ; Xin, Yong Jie ; Chen, Min-Shan ; Lu, Li Gong. / Activation of MET promotes resistance to sorafenib in hepatocellular carcinoma cells via the AKT/ERK1/2-EGR1 pathway. In: Artificial cells, nanomedicine, and biotechnology. 2019 ; Vol. 47, No. 1. pp. 83-89.
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AU - Hu, Cong

AU - Huang, Yao Ming

AU - Xiao, Jing

AU - He, Xu

AU - Xin, Yong Jie

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AU - Lu, Li Gong

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