Journal
HEPATOLOGY
Volume 64, Issue 6, Pages 2062-2076Publisher
WILEY
DOI: 10.1002/hep.28821
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Funding
- RGC CRF [CUHK8/CRF/11R, C7027-14G]
- RGC ECS [27101214]
- NSFC [81302171]
- Croucher Foundation (Croucher Innovation Award)
- Outstanding Young Researcher Award, The University of Hong Kong
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Wnt/beta-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/beta-catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3b (GSK3b), two key members of the beta-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 beta-catenin activation in liver CSCs. Conclusion: These findings uncover the noncanonical regulation of Wnt/beta-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.
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