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EPHB2 Activates β-Catenin to Enhance Cancer Stem Cell Properties and Drive Sorafenib Resistance in Hepatocellular Carcinoma.
- Source :
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Cancer research [Cancer Res] 2021 Jun 15; Vol. 81 (12), pp. 3229-3240. Date of Electronic Publication: 2021 Apr 26. - Publication Year :
- 2021
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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.)
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Apoptosis
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular metabolism
Cell Proliferation
Humans
Liver Neoplasms drug therapy
Liver Neoplasms metabolism
Liver Neoplasms pathology
Male
Mice
Mice, Inbred C57BL
Mice, SCID
Neoplastic Stem Cells metabolism
Receptor, EphB2 genetics
Tumor Cells, Cultured
Wnt Signaling Pathway
Xenograft Model Antitumor Assays
beta Catenin genetics
Carcinoma, Hepatocellular pathology
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic drug effects
Neoplastic Stem Cells pathology
Receptor, EphB2 metabolism
Sorafenib pharmacology
beta Catenin metabolism
Subjects
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