title: Wnt/β-catenin signalling maintains self-renewal and tumourigenicity of head and neck squamous cell carcinoma stem-like cells by activating Oct4.
abstract: 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/β-catenin signalling is essential for stem cell regulation and tumourigenesis, but its molecular mechanism in HNSCC CSCs remains unknown. We investigated whether Wnt/β-catenin signalling regulates self-renewal and tumourigenicity of HNSCC stem-like cells in vitro and in vivo. Cytoplasmic/nuclear β-catenin, a major effector of Wnt/β-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 β-catenin increased proliferation of HNSCC cells and induced dedifferentiation of these cells to cells with stem-like features. Knockdown of β-catenin in HNSCC stem-like cells blocked their self-renewal capacity, stemness-associated gene expression, chemoresistance, and in vivo tumourigenicity. Furthermore, β-catenin directly regulates Oct4 transcription in HNSCC stem-like cells. In addition, the effect of shRNA-mediated repression of β-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 β-catenin and Oct4 correlated with the worst prognosis. These results suggest inhibition of Wnt/β-catenin signalling as a novel therapeutic strategy for targeting HNSCC stem-like cells.
authors.affiliation: Department of Otorhinolaryngology - Head & Neck Surgery, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea.
authors.forename: Sang Hyuk
authors.initials: SH
authors.lastname: Lee
authors.forename: Bon Seok
authors.initials: BS
authors.lastname: Koo
authors.forename: Jin Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Songmei
authors.initials: S
authors.lastname: Huang
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Rho
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Bae
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kang
authors.forename: Young Sook
authors.initials: YS
authors.lastname: Kim
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Moon
authors.forename: Young Chang
authors.initials: YC
authors.lastname: Lim
mesh_terms: D063646:Carcinogenesis; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000628:therapy; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000473:pathology* / Q000628:therapy; D006801:Humans; D014411:Neoplastic Stem Cells / Q000473:pathology*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Oct4; Wnt/β-catenin signalling; cancer stem cells; head and neck cancer; target therapy