National Human Genome Research Institute, Room 5140, Building 50, 50 South Drive, MSC 8000, Bethesda, MD 20892-8000, USA.
Mol Cancer Res. 2010 Nov;8(11):1513-25. doi: 10.1158/1541-7786.MCR-10-0262. Epub 2010 Oct 13.
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.
具有血小板反应蛋白结构域的解整合素金属蛋白酶 (ADAMTS) 基因被认为是肿瘤抑制因子，因为在各种癌症中发现它们被表观遗传沉默。我们对人类黑色素瘤中的 ADAMTS 基因家族进行了突变分析，发现很大一部分黑色素瘤存在体细胞突变。为了评估最常突变的基因 ADAMTS18 的功能后果，我们对其 6 个突变进行了生物学研究。ADAMTS18 突变在标准条件下对黑色素瘤细胞生长几乎没有影响，但降低了细胞对生长因子的依赖性。ADAMTS18 突变还降低了细胞与层粘连蛋白的黏附性，并增加了体外迁移和体内转移。表达突变型 ADAMTS18 的黑色素瘤细胞在短发夹 RNA 介导的 ADAMTS18 敲低后，细胞迁移减少，这表明 ADAMTS18 突变促进黑色素瘤的生长、迁移和转移。
