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Octamer 4/microRNA‐1246 signaling axis drives Wnt/β‐catenin activation in liver cancer stem cells
Author(s) -
Chai Stella,
Ng KaiYu,
Tong Man,
Lau Eunice Y.,
Lee Terence K.,
Chan Kwok Wah,
Yuan YunFei,
Cheung TanTo,
Cheung SiuTim,
Wang XiaoQi,
Wong Nathalie,
Lo ChungMau,
Man Kwan,
Guan XinYuan,
Ma Stephanie
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28821
Subject(s) - axin2 , wnt signaling pathway , cancer research , cancer stem cell , microrna , hepatology , metastasis , cancer , catenin , stem cell , beta catenin , gsk3b , biology , signal transduction , gsk 3 , medicine , microbiology and biotechnology , biochemistry , gene
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. (H epatology 2016;64:2062‐2076).