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

被引：39

作者：

Chen, Yu ^{[1
]}

Wei, Xufeng ^{[3
]}

Guo, Changcun ^{[1
]}

Jin, Haifeng ^{[1
]}

Han, Zheyi ^{[1
]}

Han, Ying ^{[1
]}

Qiao, Taidong ^{[1
]}

Wu, Kaichun ^{[1
]}

Fan, Daiming ^{[1
,2
]}

机构：

[1] Fourth Mil Med Univ, State Key Lab Canc Biol, Xijing Hosp, Xian 710032, Shaanxi, Peoples R China

[2] Fourth Mil Med Univ, Dept Digest Dis, Xijing Hosp, Inst Digest Dis, Xian 710032, Shaanxi, Peoples R China

[3] Fourth Mil Med Univ, Dept Cardiac Surg, Xijing Hosp, Xian 710032, Shaanxi, Peoples R China

来源：

INTERNATIONAL JOURNAL OF CANCER | 2011年 / 129卷 / 07期

基金：

中国国家自然科学基金;

关键词：

RUNX3; TIMP-1; metastasis; gastric cancer; LYMPH-NODE METASTASIS; MATRIX METALLOPROTEINASES; TISSUE INHIBITOR; GROWTH-FACTOR; PROMOTER HYPERMETHYLATION; BREAST-CANCER; GELATINASE-B; EXPRESSION; ANGIOGENESIS; CARCINOMA;

D O I：

10.1002/ijc.25831

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：1586 / 1598

页数：13

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