EPHB2 activates β-catenin to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma

Hoi Wing Leung, Oi Ning Leung, Eunice Yuen Ting Lau, Po Sin Chung, Ho Kit Mok, Mang Leng Lei, Wing Hei Leung, Man Tong, Wee-Keong Vincent Keng (Corresponding Author), Cong Ma (Corresponding Author), Qian Zhao (Corresponding Author), Irene Oi Lin Ng, Stephanie Ma, Kin Wah Lee (Corresponding Author)

Research output: Journal article publicationJournal articleAcademic researchpeer-review

54 Citations (Scopus)


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 sorafenibresistant, 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 themost 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 EPHB2- High 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.

Original languageEnglish
Pages (from-to)3229-3240
Number of pages12
JournalCancer Research
Issue number12
Publication statusPublished - Jun 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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