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

DC Field Value Language
dc.contributor.author라선영-
dc.date.accessioned2015-12-28T11:04:51Z-
dc.date.available2015-12-28T11:04:51Z-
dc.date.issued2014-
dc.identifier.issn1541-7786-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/138650-
dc.description.abstractA 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.-
dc.description.statementOfResponsibilityopen-
dc.format.extent228~238-
dc.relation.isPartOfMOLECULAR CANCER RESEARCH-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHADAM Proteins/genetics*-
dc.subject.MESHADAM Proteins/metabolism*-
dc.subject.MESHADAMTS Proteins-
dc.subject.MESHApoptosis-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHCells, Cultured-
dc.subject.MESHChromosomes, Human, Pair 11-
dc.subject.MESHCpG Islands-
dc.subject.MESHDNA Methylation*-
dc.subject.MESHEpigenesis, Genetic-
dc.subject.MESHGene Expression Regulation, Neoplastic-
dc.subject.MESHGene Silencing-
dc.subject.MESHHumans-
dc.subject.MESHMAP Kinase Signaling System/drug effects*-
dc.subject.MESHNeoplasms/genetics-
dc.subject.MESHNeoplasms/metabolism*-
dc.titleThe metalloprotease ADAMTS8 displays antitumor properties through antagonizing EGFR-MEK-ERK signaling and is silenced in carcinomas by CpG methylation.-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Internal Medicine (내과학)-
dc.contributor.googleauthorGigi C.G. Choi-
dc.contributor.googleauthorJisheng Li-
dc.contributor.googleauthorYajun Wang-
dc.contributor.googleauthorLili Li-
dc.contributor.googleauthorLan Zhong-
dc.contributor.googleauthorBrigette Ma-
dc.contributor.googleauthorXianwei Su-
dc.contributor.googleauthorJianming Ying-
dc.contributor.googleauthorTingxiu Xiang-
dc.contributor.googleauthorSun Young Rha-
dc.contributor.googleauthorJun Yu-
dc.contributor.googleauthorJoseph J.Y. Sung-
dc.contributor.googleauthorSai Wah Tsao-
dc.contributor.googleauthorAnthony T.C. Chan-
dc.contributor.googleauthorQian Tao-
dc.identifier.doi10.1158/1541-7786.MCR-13-0195-
dc.admin.authorfalse-
dc.admin.mappingfalse-
dc.contributor.localIdA01316-
dc.relation.journalcodeJ02253-
dc.identifier.eissn1557-3125-
dc.identifier.pmid24184540-
dc.contributor.alternativeNameRha, Sun Young-
dc.contributor.affiliatedAuthorRha, Sun Young-
dc.citation.volume12-
dc.citation.number2-
dc.citation.startPage228-
dc.citation.endPage238-
dc.identifier.bibliographicCitationMOLECULAR CANCER RESEARCH, Vol.12(2) : 228-238, 2014-
dc.identifier.rimsid38466-
dc.type.rimsART-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers

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