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. 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.
State Key Laboratory of Cancer Biology and Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
Yu
Y
Chen
Xufeng
X
Wei
Changcun
C
Guo
Haifeng
H
Jin
Zheyi
Z
Han
Ying
Y
Han
Taidong
T
Qiao
Kaichun
K
Wu
Daiming
D
Fan
D000818:Animals; D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D015854:Up-Regulation
D050677:Core Binding Factor Alpha 3 Subunit; C493729:Runx3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9