Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter

被引：75

作者：

Hannigan, Adele ^{[1
]}

Smith, Paul ^{[2
]}

Kalna, Gabriela ^{[1
]}

Lo Nigro, Cristiana ^{[3
]}

Orange, Clare ^{[4
]}

O'Brien, Darren I. ^{[1
]}

Shah, Reshma ^{[2
]}

Syed, Nelofer ^{[2
]}

Spender, Lindsay C. ^{[1
]}

Herrera, Blanca ^{[1
]}

Thurlow, Johanna K. ^{[1
]}

Lattanzio, Laura ^{[3
]}

Monteverde, Martino ^{[3
]}

Maurer, Meghan E. ^{[5
]}

Buffa, Francesca M. ^{[6
]}

Mann, Jelena ^{[7
]}

Chu, David C. K. ^{[8
]}

West, Catharine M. L. ^{[9
]}

Patridge, Max ^{[10
,11
,12
]}

Oien, Karin A. ^{[4
]}

Cooper, Jonathan A. ^{[5
]}

Frame, Margaret C. ^{[13
]}

Harris, Adrian L. ^{[6
]}

Hiller, Louise ^{[14
]}

Nicholson, Linda J. ^{[15
]}

Gasco, Milena ^{[3
]}

Crook, Tim ^{[2
]}

Inman, Gareth J. ^{[1
]}

机构：

[1] Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland

[2] Inst Canc Res, Canc Genet & Epigenet Lab, London SW3 6JB, England

[3] Osped Santa Croce & Carle, Dept Med Oncol, Cuneo, Italy

[4] Univ Glasgow, Fac Med, Div Canc Sci & Mol Pathol, Glasgow, Lanark, Scotland

[5] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[6] Univ Oxford, Weatherall Inst Mol Med, CRUK Mol Oncol Labs, Oxford, England

[7] Newcastle Univ, Fac Med Sci, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[8] Univ Georgia, Coll Pharm, Athens, GA 30602 USA

[9] Christie Hosp NHS Trust, Sch Canc & Enabling Sci, Manchester M20 4BX, Lancs, England

[10] Guys Hosp, Univ London Kings Coll, Dept Oral & Maxillofacial Surg, London SE1 9RT, England

[11] Kings Hosp, Univ London Kings Coll, Dept Oral & Maxillofacial Surg, London, England

[12] St Thomas Hosp, Univ London Kings Coll, Dept Oral & Maxillofacial Surg, London, England

[13] Western Gen Hosp, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[14] Univ Warwick, Warwick Med Sch, Clin Trials Unit, Coventry CV4 7AL, W Midlands, England

[15] St Thomas Hosp, Univ London Kings Coll, Sch Med, Canc Studies Div,Rayne Inst, London, England

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2010年 / 120卷 / 08期

关键词：

GROWTH-FACTOR-BETA; CHEMICALLY TRANSFORMED-CELLS; BREAST-CANCER; ADAPTER PROTEIN; DAB2; GENE; METASTASIS; EXPRESSION; RECEPTORS; PATHWAY;

D O I：

10.1172/JCI36125

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

The cytokine TGF-beta acts as a tumor suppressor in normal epithelial cells and during the early stages of tumorigenesis. During malignant progression, cancer cells can switch their response to TGF-beta and use this cytokine as a potent oncogenic factor; however, the mechanistic basis for this is poorly understood. Here we demonstrate that downregulation of disabled homolog 2 (DAB2) gene expression via promoter methylation frequently occurs in human squamous cell carcinomas (SCCs) and acts as an independent predictor of metastasis and poor prognosis. Retrospective microarray analysis in an independent data set indicated that low levels of DAB2 and high levels of TGFB2 expression correlate with poor prognosis. Immunohistochemistry, reexpression, genetic knockout, and RNAi silencing studies demonstrated that downregulation of DAB2 expression modulated the TGF-beta/Smad pathway. Simultaneously, DAB2 down-regulation abrogated TGF-beta tumor suppressor function, while enabling TGF-beta tumor-promoting activities. Downregulation of DAB2 blocked TGF-beta-mediated inhibition of cell proliferation and migration and enabled TGF-beta to promote cell motility, anchorage-independent growth, and tumor growth in vivo. Our data indicate that DAB2 acts as a tumor suppressor by dictating tumor cell TGF-beta responses, identify a biomarker for SCC progression, and suggest a means to stratify patients with advanced SCC who may benefit clinically from anti-TGF-beta therapies.

引用

页码：2842 / 2857

页数：16

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