Runx3 suppresses gastric cancer metastasis through inactivation of MMP9 by upregulation of TIMP‐1

Recent studies have suggested that loss of RUNX3 expression is involved with gastric tumor metastasis. However, the precise mechanism of RUNX3‐mediated suppression of tumor metastasis remains elusive. We aimed to clarify the effect of RUNX3 on tumor metastasis in gastric cancer cell lines and tumors...

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Bibliographic Details
Published in:International journal of cancer 2011-10, Vol.129 (7), p.1586-1598
Main Authors: Chen, Yu, Wei, Xufeng, Guo, Changcun, Jin, Haifeng, Han, Zheyi, Han, Ying, Qiao, Taidong, Wu, Kaichun, Fan, Daiming
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Line, Tumor
Core Binding Factor Alpha 3 Subunit - genetics
Core Binding Factor Alpha 3 Subunit - metabolism
Female
gastric cancer
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression Regulation, Neoplastic
Humans
Matrix Metalloproteinase 9 - metabolism
Medical sciences
metastasis
Mice
Mice, Nude
Neoplasm Metastasis - prevention & control
RUNX3
Stomach Neoplasms - genetics
Stomach Neoplasms - pathology
Stomach. Duodenum. Small intestine. Colon. Rectum. Anus
TIMP‐1
Tissue Inhibitor of Metalloproteinase-1 - metabolism
Tumors
Up-Regulation
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Summary:Recent studies have suggested that loss of RUNX3 expression is involved with gastric tumor metastasis. However, the precise mechanism of RUNX3‐mediated suppression of tumor metastasis remains elusive. We aimed to clarify the effect of RUNX3 on tumor metastasis in gastric cancer cell lines and tumors. Immunohistochemistry revealed that RUNX3 was significantly decreased in metastatic gastric cancer. Gelatin zymography and Western blot showed that instead of regulating matrix metalloproteinase 9 (MMP9) expression, RUNX3 expression inhibited MMP9 enzyme activity, and this was consistent with the upregulation of tissue inhibitor of metalloproteinases 1 (TIMP1) by RUNX3. TIMP1 siRNA treatment impaired RUNX3‐mediated suppression of gastric cancer cell invasion. Reporter assays demonstrated regulation of TIMP‐1 by RUNX3. Two RUNX3 binding sites were identified in the TIMP‐1 promoter and direct interaction of RUNX3 with the TIMP‐1 promoter was confirmed in vitro and in vivo. These findings provide evidence for RUNX3‐mediated suppression of gastric cancer invasion and metastasis and define a novel molecular mechanism that for the metastasis‐inhibiting activity of RUNX3. These data may be applied in the development of RUNX3 for gastric cancer metastasis diagnostics and therapeutics.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.25831