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

被引:123
作者
Lee, Sang Hyuk [1 ]
Koo, Bon Seok [2 ]
Kim, Jin Man [3 ]
Huang, Songmei [3 ]
Rho, Young Soo [4 ]
Bae, Woo Jin [5 ]
Kang, Hyun Jung [6 ]
Kim, Young Sook [6 ]
Moon, Jung Hwa [6 ]
Lim, Young Chang [6 ]
机构
[1] Sungkyunkwan Univ, Sch Med, Kangbuk Samsung Hosp, Dept Otorhinolaryngol Head & Neck Surg, Seoul, South Korea
[2] Chungnam Natl Univ, Dept Otolaryngol Head & Neck Surg, Canc Res Inst, Coll Med, Taejon, South Korea
[3] Chungnam Natl Univ, Dept Pathol, Res Inst Med Sci & Pathol, Coll Med, Taejon, South Korea
[4] Ewha Womans Univ, Dept Otorhinolaryngol Head & Neck Surg, Sch Med, Seoul, South Korea
[5] Hallym Univ, Dept Otolaryngol Head & Neck Surg, Coll Med, Seoul, South Korea
[6] Konkuk Univ, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Res Inst Med Sci, Seoul 143752, South Korea
基金
新加坡国家研究基金会;
关键词
head and neck cancer; cancer stem cells; Wnt/beta-catenin signalling; Oct4; target therapy; CANCER CELLS; DRUG-RESISTANCE; BLADDER-CANCER; BETA-CATENIN; EXPRESSION; MARKER; KERATINOCYTES; PROGRESSION; PATHWAY; SKIN;
D O I
10.1002/path.4383
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:99 / 107
页数:9
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