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The metalloprotease ADAMTS8 displays antitumor properties through antagonizing EGFR-MEK-ERK signaling and is silenced in carcinomas by CpG methylation.

Authors
 Gigi C.G. Choi  ;  Jisheng Li  ;  Yajun Wang  ;  Lili Li  ;  Lan Zhong  ;  Brigette Ma  ;  Xianwei Su  ;  Jianming Ying  ;  Tingxiu Xiang  ;  Sun Young Rha  ;  Jun Yu  ;  Joseph J.Y. Sung  ;  Sai Wah Tsao  ;  Anthony T.C. Chan  ;  Qian Tao 
Citation
 MOLECULAR CANCER RESEARCH, Vol.12(2) : 228-238, 2014 
Journal Title
MOLECULAR CANCER RESEARCH
ISSN
 1541-7786 
Issue Date
2014
MeSH
ADAM Proteins/genetics* ; ADAM Proteins/metabolism* ; ADAMTS Proteins ; Apoptosis ; Cell Line, Tumor ; Cells, Cultured ; Chromosomes, Human, Pair 11 ; CpG Islands ; DNA Methylation* ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic ; Gene Silencing ; Humans ; MAP Kinase Signaling System/drug effects* ; Neoplasms/genetics ; Neoplasms/metabolism*
Abstract
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.
IMPLICATIONS: This study uncovers the tumor suppressive function of ADAMTS8, one of the ADAMTS family members, and its frequent methylation in certain tumors could be developed as a potential biomarker.
Files in This Item:
T201405189.pdf Download
DOI
10.1158/1541-7786.MCR-13-0195
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/138650
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