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The effect of disintegrin-metalloproteinase ADAM9 in gastric cancer progression.

 Jeong Min Kim  ;  Hei Cheul Jeung  ;  Sun Young Rha  ;  Eun Jeong Yu  ;  Tae Soo Kim  ;  You Keun Shin  ;  Xianglan Zhang  ;  Kyu Hyun Park  ;  Seung Woo Park  ;  Hyun Cheol Chung  ;  Garth Powis 
 MOLECULAR CANCER THERAPEUTICS, Vol.13(12) : 3074-3085, 2014 
Journal Title
Issue Date
ADAM Proteins/antagonists & inhibitors ; ADAM Proteins/genetics ; ADAM Proteins/metabolism* ; Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacology ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Disease Models, Animal ; Disease Progression ; Disintegrins/metabolism* ; Enzyme Activation ; Female ; Gene Expression ; Gene Expression Profiling ; Heterografts ; Humans ; Hypoxia/metabolism ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/genetics ; Membrane Proteins/metabolism* ; Mice ; Neoplasm Invasiveness ; Protein Binding ; RNA Interference ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/genetics ; Stomach Neoplasms/metabolism* ; Stomach Neoplasms/pathology* ; Tumor Burden/drug effects
Advanced gastric cancer is one of the most aggressive gastrointestinal malignancies, and ADAM (A disintegrin and metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biologic mechanism of ADAM9 in the progression, proliferation, and invasion of gastric cancer. First, we detected ADAM's expression, processing, and protease activity in gastric cancer cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockdown of ADAM9 or specifically targeted monoclonal antibody (RAV-18) suppressed cancer cell proliferation and invasion in high ADAM9-expressing cells, not in low ADAM9-expressing cells. RAV-18 showed in vivo antitumor activity in a gastric cancer xenograft model. Hypoxia (1% oxygen) induced ADAM9 expression and functional activity in low ADAM9-expressing gastric cancer cells that was inhibited by siRNA knockdown or RAV-18 antibody to levels in normoxic cells. Overall, our studies show that ADAM9 plays an important role in gastric cancer proliferation and invasion, and that while expressed in some gastric cancer cells at high levels that are responsive to functional inhibition and antitumor activity of a catalytic site-directed antibody, other gastric cancer cells have low levels of expression and only when exposed to hypoxia do ADAM9 levels increase and the cells become responsive to ADAM9 antibody inhibition. Therefore, our findings suggest that ADAM9 could be an effective therapeutic target for advanced gastric cancer.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소) > 1. Journal Papers
Yonsei Authors
Kim, Jung Min(김정민)
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Park, Seung Woo(박승우) ORCID logo https://orcid.org/0000-0001-8230-964X
Shin, You Keun(신유근)
Yu, Eun Jeong(유은정)
Zhang, Xiang Lan(장향란)
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
Jeung, Hei Cheul(정희철) ORCID logo https://orcid.org/0000-0003-0952-3679
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