The metalloprotease adamts8 displays antitumor properties through antagonizing egfr-mek-erk signaling and is silenced in carcinomas by cpg methylation

Gigi C.G. Choi, Jisheng Li, Yajun Wang, Lili Li, Lan Zhong, Brigette Ma, Xianwei Su, Jianming Ying, Tingxiu Xiang, SunYoung Rha, Jun Yu, Joseph J.Y. Sung, Sai Wah Tsao, Anthony T.C. Chan, Qian Tao

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Abstract

A disintegrins and metalloproteinases with thrombospondinmotifs (ADAMTS) familymembers 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.ADAMTS8as 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. Mol Cancer Res; 12(2); 228-38.

Original languageEnglish
Pages (from-to)228-238
Number of pages11
JournalMolecular Cancer Research
Volume12
Issue number2
DOIs
Publication statusPublished - 2014 Feb 1

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Metalloproteases
Methylation
Carcinoma
Neoplasms
Disintegrins
Mitogen-Activated Protein Kinase Kinases
Epidermal Growth Factor Receptor
Down-Regulation
Stress Fibers
Loss of Heterozygosity
Tumor Suppressor Genes
Cell Movement
Actins
Colorectal Neoplasms
Stomach
Peptide Hydrolases
Biomarkers
Apoptosis
Cell Line

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Choi, Gigi C.G. ; Li, Jisheng ; Wang, Yajun ; Li, Lili ; Zhong, Lan ; Ma, Brigette ; Su, Xianwei ; Ying, Jianming ; Xiang, Tingxiu ; Rha, SunYoung ; Yu, Jun ; Sung, Joseph J.Y. ; Tsao, Sai Wah ; Chan, Anthony T.C. ; Tao, Qian. / The metalloprotease adamts8 displays antitumor properties through antagonizing egfr-mek-erk signaling and is silenced in carcinomas by cpg methylation. In: Molecular Cancer Research. 2014 ; Vol. 12, No. 2. pp. 228-238.
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abstract = "A disintegrins and metalloproteinases with thrombospondinmotifs (ADAMTS) familymembers 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.ADAMTS8as 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. Mol Cancer Res; 12(2); 228-38.",
author = "Choi, {Gigi C.G.} and Jisheng Li and Yajun Wang and Lili Li and Lan Zhong and Brigette Ma and Xianwei Su and Jianming Ying and Tingxiu Xiang and SunYoung Rha and Jun Yu and Sung, {Joseph J.Y.} and Tsao, {Sai Wah} and Chan, {Anthony T.C.} and Qian Tao",
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Choi, GCG, Li, J, Wang, Y, Li, L, Zhong, L, Ma, B, Su, X, Ying, J, Xiang, T, Rha, S, Yu, J, Sung, JJY, Tsao, SW, Chan, ATC & Tao, Q 2014, 'The metalloprotease adamts8 displays antitumor properties through antagonizing egfr-mek-erk signaling and is silenced in carcinomas by cpg methylation', Molecular Cancer Research, vol. 12, no. 2, pp. 228-238. https://doi.org/10.1158/1541-7786.MCR-13-0195

The metalloprotease adamts8 displays antitumor properties through antagonizing egfr-mek-erk signaling and is silenced in carcinomas by cpg methylation. / Choi, Gigi C.G.; Li, Jisheng; Wang, Yajun; Li, Lili; Zhong, Lan; Ma, Brigette; Su, Xianwei; Ying, Jianming; Xiang, Tingxiu; Rha, SunYoung; Yu, Jun; Sung, Joseph J.Y.; Tsao, Sai Wah; Chan, Anthony T.C.; Tao, Qian.

In: Molecular Cancer Research, Vol. 12, No. 2, 01.02.2014, p. 228-238.

Research output: Contribution to journalArticle

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T1 - The metalloprotease adamts8 displays antitumor properties through antagonizing egfr-mek-erk signaling and is silenced in carcinomas by cpg methylation

AU - Choi, Gigi C.G.

AU - Li, Jisheng

AU - Wang, Yajun

AU - Li, Lili

AU - Zhong, Lan

AU - Ma, Brigette

AU - Su, Xianwei

AU - Ying, Jianming

AU - Xiang, Tingxiu

AU - Rha, SunYoung

AU - Yu, Jun

AU - Sung, Joseph J.Y.

AU - Tsao, Sai Wah

AU - Chan, Anthony T.C.

AU - Tao, Qian

PY - 2014/2/1

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N2 - A disintegrins and metalloproteinases with thrombospondinmotifs (ADAMTS) familymembers 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.ADAMTS8as 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. Mol Cancer Res; 12(2); 228-38.

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