Octamer 4/MicroRNA-1246 Signaling Axis Drives Wnt/β-Catenin Activation in Liver Cancer Stem Cells

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.