Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/90294
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dc.contributorDepartment of Applied Biology and Chemical Technologyen_US
dc.creatorLeung, HWen_US
dc.creatorLeung, CONen_US
dc.creatorLau, EYen_US
dc.creatorChung, KPSen_US
dc.creatorMok, EHen_US
dc.creatorLei, MMLen_US
dc.creatorLeung, RWHen_US
dc.creatorTong, Men_US
dc.creatorKeng, VWen_US
dc.creatorMa, Cen_US
dc.creatorZhao, Qen_US
dc.creatorNg, IOLen_US
dc.creatorMa, Sen_US
dc.creatorLEE, TKen_US
dc.date.accessioned2021-06-10T06:54:53Z-
dc.date.available2021-06-10T06:54:53Z-
dc.identifier.issn0008-5472en_US
dc.identifier.urihttp://hdl.handle.net/10397/90294-
dc.language.isoenen_US
dc.publisherAmerican Association for Cancer Researchen_US
dc.rights©2021 American Association for Cancer Research.en_US
dc.rightsThis manuscript has been accepted for publication in Molecular Biotechnology, which is published by the American Association for Cancer Research. The final published version of record is available at https://dx.doi.org/10.1158/0008-5472.CAN-21-0184en_US
dc.titleEPHB2 activates β-catenin to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinomaen_US
dc.typeJournal/Magazine Articleen_US
dc.identifier.spage3329en_US
dc.identifier.epage3340en_US
dc.identifier.volume81en_US
dc.identifier.issue12en_US
dc.identifier.doi10.1158/0008-5472.CAN-21-0184en_US
dcterms.abstractThe 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.en_US
dcterms.accessRightsopen accessen_US
dcterms.bibliographicCitationCancer research, 15 June 2021, v. 81, no. 12, p. 3229-3240.en_US
dcterms.isPartOfCancer researchen_US
dcterms.issued2021-06-15-
dc.identifier.eissn1538-7445en_US
dc.description.validate202106 bcvcen_US
dc.description.oaAuthor’s Originalen_US
dc.identifier.FolderNumbera0913-n01-
dc.identifier.SubFormID2128-
dc.description.fundingSourceRGCen_US
dc.description.fundingTextRGC GRF 15103817, Theme-based Research Scheme project (T12-704/16-R )en_US
dc.description.pubStatusPublisheden_US
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