Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis

被引：216

作者：

Darido, Charbel ^{[1
]}

Georgy, Smitha R. ^{[1
]}

Wilanowski, Tomasz ^{[2
]}

Dworkin, Sebastian ^{[1
]}

Auden, Alana ^{[1
]}

Zhao, Quan ^{[1
]}

Rank, Gerhard ^{[1
]}

Srivastava, Seema ^{[1
]}

Finlay, Moira J. ^{[3
]}

Papenfuss, Anthony T. ^{[4
]}

Pandolfi, Pier Paolo ^{[5
,6
]}

Pearson, Richard B. ^{[7
,8
,9
]}

Jane, Stephen M. ^{[1
,10
]}

机构：

[1] Monash Univ, Cent Clin Sch, Dept Med, Prahran, Vic 3181, Australia

[2] Polish Acad Sci, Nencki Inst Expt Biol, Lab Signal Transduct, PL-02093 Warsaw, Poland

[3] Royal Melbourne Hosp, Dept Pathol, Parkville, Vic 3050, Australia

[4] Walter & Eliza Hall Inst Med Res, Div Bioinformat, Parkville, Vic, Australia

[5] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Genet Program, Boston, MA 02215 USA

[6] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol & Med, Boston, MA 02215 USA

[7] Peter MacCallum Canc Ctr, Growth Control & Differentiat Program, Melbourne, Vic 3002, Australia

[8] Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3050, Australia

[9] Univ Melbourne, Dept Med, Parkville, Vic 3050, Australia

[10] Alfred Hosp, Prahran, Vic 3181, Australia

来源：

CANCER CELL | 2011年 / 20卷 / 05期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

B-KINASE-ALPHA; NONMELANOMA SKIN-CANCER; MICE LACKING; IKK-ALPHA; EXPRESSION SIGNATURE; TRANSCRIPTION FACTOR; NEGATIVE REGULATION; WOUND REPAIR; GRAINY-HEAD; MOUSE;

D O I：

10.1016/j.ccr.2011.10.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of P131K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC.

引用

页码：635 / 648

页数：14

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