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

ABSTRACT

Wnt/ß-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/ß-catenin pathway through suppressing the expression of AXIN2 and glycogen synthase kinase 3ß (GSK3ß), two key members of the ß-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 ß-catenin activation in liver CSCs. CONCLUSION: These findings uncover the noncanonical regulation of Wnt/ß-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;642062-2076).