Stella Chai1, Kai-Yu Ng1, Man Tong1, Eunice Y Lau2, Terence K Lee2, Kwok Wah Chan3, Yun-Fei Yuan4, Tan-To Cheung5, Siu-Tim Cheung6, Xiao-Qi Wang5, Nathalie Wong7, Chung-Mau Lo5,8, Kwan Man5,8, Xin-Yuan Guan9,8, Stephanie Ma1,8. 1. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. 2. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong. 3. Departments of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. 4. State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China. 5. Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. 6. Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong. 7. Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong. 8. State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. 9. Department of Clincial Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
Abstract
Wnt/β-catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR-1246, promotes cancer stemness, including self-renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β-catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β-catenin destruction complex. Clinically, high endogenous and circulating miR-1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR-1246, which cooperatively drive β-catenin activation in liver CSCs. CONCLUSION: These findings uncover the noncanonical regulation of Wnt/β-catenin in liver CSCs by the Oct4/miR-1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062-2076).
Wnt/β-catenin signaling is activated in CD133 liver cancer stem cells (CSCs), a subset of cells known to be a root of tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the regulatory mechanism of this pathway in CSCs remains unclear. Here, we show that human microRNA (miRNA), miR-1246, promotes cancer stemness, including self-renewal, drug resistance, tumorigencity, and metastasis, by activation of the Wnt/β-catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3β (GSK3β), two key members of the β-catenin destruction complex. Clinically, high endogenous and circulating miR-1246 was identified in HCC clinical samples and correlated with a worse prognosis. Further functional analysis identified octamer 4 (Oct4) to be the direct upstream regulator of miR-1246, which cooperatively drive β-catenin activation in liver CSCs. CONCLUSION: These findings uncover the noncanonical regulation of Wnt/β-catenin in liver CSCs by the Oct4/miR-1246 signaling axis, and also provide a novel diagnostic marker as well as therapeutic intervention for HCC. (Hepatology 2016;64:2062-2076).
Authors: Bei Xie; Linjing Li; Zhewen Zhang; Lei Zhao; Juan Cheng; Cunmin Zhou; Jie Cheng; Jing Yan; Jing Chen; Juan Yi; Bei Wang; Suya Jin; Hulai Wei Journal: J Cancer Date: 2021-05-13 Impact factor: 4.207