Please use this identifier to cite or link to this item:
http://hdl.handle.net/10397/90294
Title: | 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 |
Issue Date: | 15-Jun-2021 | Source: | Cancer research, 15 June 2021, v. 81, no. 12, p. 3229-3240. | 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 HCC patients. RNA-sequencing analysis of sorafenib-resistant PDXs and their corresponding mock controls identified 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 EPHB2Low 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. | Publisher: | American Association for Cancer Research | Journal: | Cancer research | ISSN: | 0008-5472 | EISSN: | 1538-7445 | DOI: | 10.1158/0008-5472.CAN-21-0184 | Rights: | ©2021 American Association for Cancer Research. The following publication Leung, H. W., Leung, C. O. N., Lau, E. Y., Chung, K. P. S., Mok, E. H., Lei, M. M. L., . . . Lee, T. K. (2021). EPHB2 activates β-catenin to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma. Cancer Research, 81(12), 3229-3240 is available at https://dx.doi.org/10.1158/0008-5472.CAN-21-0184. |
Appears in Collections: | Journal/Magazine Article |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Leung_et_al._EPHB2_Cancer_Research.pdf | Pre-Published version | 488.14 kB | Adobe PDF | View/Open |
Page views
97
Last Week
0
0
Last month
Citations as of Apr 28, 2024
Downloads
42
Citations as of Apr 28, 2024
SCOPUSTM
Citations
60
Citations as of Apr 26, 2024
WEB OF SCIENCETM
Citations
56
Citations as of May 2, 2024
Google ScholarTM
Check
Altmetric
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.