Wnt/β-catenin signalling maintains self-renewal and tumourigenicity of head and neck squamous cell carcinoma stem-like cells by activating Oct4.

Accumulating evidence suggests that a distinct subpopulation of cancer stem cells (CSCs) is responsible for tumour initiation and progression in head and neck squamous cell carcinoma (HNSCC). Wnt/beta-catenin signalling is essential for stem cell regulation and tumourigenesis, but its molecular mechanism in HNSCC CSCs remains unknown. We investigated whether Wnt/beta-catenin signalling regulates self-renewal and tumourigenicity of HNSCC stem-like cells in vitro and in vivo. Cytoplasmic/nuclear beta-catenin, a major effector of Wnt/beta-catenin signalling, was expressed in a subpopulation of tumour cells in primary HNSCC tissue but in none of normal head and neck tissues. Overexpression of beta-catenin increased proliferation of HNSCC cells and induced dedifferentiation of these cells to cells with stem-like features. Knockdown of beta-catenin in HNSCC stem-like cells blocked their self-renewal capacity, stemness-associated gene expression, chemoresistance, and in vivo tumourigenicity. Furthermore, beta-catenin directly regulates Oct4 transcription in HNSCC stem-like cells. In addition, the effect of shRNA-mediated repression of beta-catenin on CSC traits in HNSCC stem-like cells was reversed by overexpression of Oct4. In patients with HNSCC, higher levels of both cytoplasmic/nuclear beta-catenin and Oct4 correlated with the worst prognosis. These results suggest inhibition of Wnt/beta-catenin signalling as a novel therapeutic strategy for targeting HNSCC stem-like cells. Copyright (C) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.