Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells : Hepatology

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Hepatobiliary Malignancies

Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells

Chai, Stella1; Ng, Kai‐Yu1; Tong, Man1; Lau, Eunice Y.6; Lee, Terence K.6; Chan, Kwok Wah2; Yuan, Yun‐Fei7; Cheung, Tan‐To3; Cheung, Siu‐Tim8; Wang, Xiao‐Qi3; Wong, Nathalie9; Lo, Chung‐Mau3,5; Man, Kwan3,5; Guan, Xin‐Yuan4,5; Ma, Stephanie*,1,5

Author Information

1School of Biomedical Sciences, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong

2Departments of Pathology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong

3Department of Surgery, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong

4Department of Clincial Oncology, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong

5State Key Laboratory for Liver Research, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong

6Department of Applied Biology & Chemical TechnologyThe Hong Kong Polytechnic UniversityHong Kong

7State Key Laboratory of Oncology in Southern ChinaSun Yat‐Sen University Cancer CenterGuangzhouChina

8Department of Surgery, Faculty of MedicineThe Chinese University of Hong KongHong Kong

9Department of Anatomical and Cellular Pathology, Faculty of MedicineThe Chinese University of Hong KongHong Kong

*ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Stephanie Ma, Ph.D.
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
The University of Hong Kong
1/F Laboratory Block
21 Sassoon Road
Pok Fu Lam
Hong Kong
E‐mail: [email protected]
Tel: 852‐3917‐9238

Hepatology 64(6):p 2062-2076, December 2016. | DOI: 10.1002/hep.28821

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).

© 2016 by the American Association for the Study of Liver Diseases.

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