Mutational and Functional Analysis Reveals ADAMTS18 Metalloproteinase as a Novel Driver in Melanoma

被引：41

作者：

Wei, Xiaomu ^{[1
]}

Prickett, Todd D. ^{[1
]}

Viloria, Cristina G. ^{[4
]}

Molinolo, Alfredo ^{[2
]}

Lin, Jimmy C. ^{[5
,6
]}

Cardenas-Navia, Isabel ^{[1
]}

Cruz, Pedro ^{[1
]}

Rosenberg, Steven A. ^{[3
]}

Davies, Michael A. ^{[7
,8
]}

Gershenwald, Jeffrey E. ^{[9
,10
]}

Lopez-Otin, Carlos ^{[4
]}

Samuels, Yardena ^{[1
]}

机构：

[1] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA

[2] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA

[3] NCI, NIH, Bethesda, MD 20892 USA

[4] Univ Oviedo, Dept Bioquim & Biol Mol, Inst Univ Oncol, Oviedo, Spain

[5] Johns Hopkins Kimmel Canc Ctr, Ludwig Ctr Canc Genet & Therapeut, Baltimore, MD USA

[6] Johns Hopkins Kimmel Canc Ctr, Howard Hughes Med Inst, Baltimore, MD USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

来源：

MOLECULAR CANCER RESEARCH | 2010年 / 8卷 / 11期

关键词：

PROTEOLYTIC ACTIVITIES; EMERGING ROLES; HUMAN BREAST; IDENTIFICATION; SUPPRESSOR; MULTIPLE; INACTIVATION; METASTASIS; MODULATION; ESOPHAGEAL;

D O I：

10.1158/1541-7786.MCR-10-0262

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The disintegrin-metalloproteinases with thrombospondin domains (ADAMTS) genes have been suggested to function as tumor suppressors as several have been found to be epigenetically silenced in various cancers. We performed a mutational analysis of the ADAMTS gene family in human melanoma and identified a large fraction of melanomas to harbor somatic mutations. To evaluate the functional consequences of the most commonly mutated gene, ADAMTS18, six of its mutations were biologically examined. ADAMTS18 mutations had little effect on melanoma cell growth under standard conditions, but reduced cell dependence on growth factors. ADAMTS18 mutations also reduced adhesion to laminin and increased migration in vitro and metastasis in vivo. Melanoma cells expressing mutant ADAMTS18 had reduced cell migration after short hairpin RNA-mediated knockdown of ADAMTS18, suggesting that ADAMTS18 mutations promote growth, migration, and metastasis in melanoma. Mol Cancer Res; 8(11); 1513-25. (C) 2010 AACR.

引用

页码：1513 / 1525

页数：13

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