The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR-MEK-ERK Signaling and Is Silenced in Carcinomas by CpG Methylation
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摘要A disintegrins and metalloproteinases with thrombospondin motifs (ADAMTS) family members have been reported dysregulated in various cancers. Through refining a loss of heterozygosity locus at 11q25 by array-CGH, we identified ADAMTS8 as a novel candidate tumor suppressor gene. Although ADAMTS8 downregulation has been reported in several tumors, its biologic function and underlying mechanism remain largely unknown. Here, we found that ADAMTS8 is broadly expressed in normal tissues but frequently downregulated or silenced by promoter methylation in common carcinoma cell lines, including nasopharyngeal, esophageal squamous cell, gastric, and colorectal carcinomas. Pharmacologic or genetic demethylation restored ADAMTS8 expression, indicating that promoter methylation mediates its silencing. Aberrant methylation of ADAMTS8 was also detected in several types of primary tumors but rarely in normal tissues. Further functional studies showed that restoring ADAMTS8 expression suppressed tumor cell clonogenicity through inducing apoptosis. ADAMTS8 as a secreted protease inhibited epidermal growth factor receptor (EGFR) signaling along with decreased levels of phosphorylated MEK and ERK. We further found that ADAMTS8 disrupted actin stress fiber organization and inhibited tumor cell motility. Thus, our data demonstrate that ADAMTS8 metalloprotease acts as a functional tumor suppressor through antagonizing EGFR-MEK-ERK signaling, in addition to its previously reported anti-angiogenesis function, and is frequently methylated in common tumors. (C) 2013 AACR.
著者Choi GCG, Li JS, Wang YJ, Li LL, Zhong L, Ma B, Su XW, Ying JM, Xiang TX, Rha SY, Yu J, Sung JJY, Tsao SW, Chan ATC, Tao Q
期刊名稱Molecular Cancer Research
出版年份2014
月份2
日期1
卷號12
期次2
出版社AMER ASSOC CANCER RESEARCH
頁次228 - 238
國際標準期刊號1541-7786
電子國際標準期刊號1557-3125
語言英式英語
Web of Science 學科類別Cell Biology; CELL BIOLOGY; Oncology; ONCOLOGY

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