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 language | English |
|---|---|
| Pages (from-to) | 228-238 |
| Number of pages | 11 |
| Journal | Molecular Cancer Research |
| Volume | 12 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2014 Feb 1 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Oncology
- Cancer Research
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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 journal › Article
TY - JOUR
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
Y1 - 2014/2/1
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.
AB - 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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U2 - 10.1158/1541-7786.MCR-13-0195
DO - 10.1158/1541-7786.MCR-13-0195
M3 - Article
VL - 12
SP - 228
EP - 238
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 2
ER -