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

Stella Chai, Kai Yu Ng, Man Tong, Eunice Y. Lau, Kin Wah Lee, Kwok Wah Chan, Yun Fei Yuan, Tan To Cheung, Siu Tim Cheung, Xiao Qi Wang, Nathalie Wong, Chung Mau Lo, Kwan Man, Xin Yuan Guan, Stephanie Ma

Research output: Journal article publicationJournal articleAcademic researchpeer-review

93 Citations (Scopus)

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).
Original languageEnglish
Pages (from-to)2062-2076
Number of pages15
JournalHepatology
Volume64
Issue number6
DOIs
Publication statusPublished - 1 Dec 2016

ASJC Scopus subject areas

  • Hepatology

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