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EPHB2 Activates β-Catenin to Enhance Cancer Stem Cell Properties and Drive Sorafenib Resistance in Hepatocellular Carcinoma.

Authors :
Leung HW
Leung CON
Lau EY
Chung KPS
Mok EH
Lei MML
Leung RWH
Tong M
Keng VW
Ma C
Zhao Q
Ng IOL
Ma S
Lee TK
Source :
Cancer research [Cancer Res] 2021 Jun 15; Vol. 81 (12), pp. 3229-3240. Date of Electronic Publication: 2021 Apr 26.
Publication Year :
2021

Abstract

The survival benefit derived from sorafenib treatment for patients with hepatocellular carcinoma (HCC) is modest due to acquired resistance. Targeting cancer stem cells (CSC) is a possible way to reverse drug resistance, however, inhibitors that specifically target liver CSCs are limited. In this study, we established two sorafenib-resistant, patient-derived tumor xenografts (PDX) that mimicked development of acquired resistance to sorafenib in patients with HCC. RNA-sequencing analysis of sorafenib-resistant PDXs and their corresponding mock controls identified EPH receptor B2 (EPHB2) as the most significantly upregulated kinase. EPHB2 expression increased stepwise from normal liver tissue to fibrotic liver tissue to HCC tissue and correlated with poor prognosis. Endogenous EPHB2 knockout showed attenuation of tumor development in mice. EPHB2 regulated the traits of liver CSCs; similarly, sorted EPHB2High HCC cells were endowed with enhanced CSC properties when compared with their EPHB2-Low counterparts. Mechanistically, EPHB2 regulated cancer stemness and drug resistance by driving the SRC/AKT/GSK3β/β-catenin signaling cascade, and EPHB2 expression was regulated by TCF1 via promoter activation, forming a positive Wnt/β-catenin feedback loop. Intravenous administration of rAAV-8-shEPHB2 suppressed HCC tumor growth and significantly sensitized HCC cells to sorafenib in an NRAS/AKT-driven HCC immunocompetent mouse model. Targeting a positive feedback loop involving the EPHB2/β-catenin axis may be a possible therapeutic strategy to combat acquired drug resistance in HCC. SIGNIFICANCE: This study identifies a EPHB2/β-catenin/TCF1 positive feedback loop that augments cancer stemness and sorafenib resistance in HCC, revealing a targetable axis to combat acquired drug resistance in HCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3229/F1.large.jpg.<br /> (©2021 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1538-7445
Volume :
81
Issue :
12
Database :
MEDLINE
Journal :
Cancer research
Publication Type :
Academic Journal
Accession number :
33903122
Full Text :
https://doi.org/10.1158/0008-5472.CAN-21-0184