ABSTRACT
The expression of matrix metalloproteinase-2 (MMP2) has been linked with tumor invasion, angiogenesis, and metastasis. It has been reported that angiotensin II (Ang II) can induce MMP2 expression in gastric cancer cells. However, the molecular basis for Ang II regulates MMP2 expression in gastric cancer cells remains unclear. The aim of our study is to explore whether angiotensin II could induce MMP2 expression mediated through the Stat signaling pathway and its potential mechanism. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-binding assays was employed to determine the DNA-STAT binding activity. MMP2 and VEGF expression was analyzed with real-time PCR and Western blots. To examine the role of Stat3 in angiotensin II-induced MMP2 expression, A JAK-specific inhibitor and AG490 were used. Angiotensin II activated STAT-DNA binding activity in dose-dependent manners in gastric cancer cells. AG490 markedly inhibited angiotensin II-induced Stat3 activation and the expression of MMP2 and VEGF in gastric cancer cells. These results indicate that Stat3 may at least in part mediate angiotensin II-induced MMP2 mRNA expression in human gastric cancer cells. The activation of the JAK/Stat3 signaling pathway plays an important role in the progression of gastric cancer and that blockade of JAK/Stat3 signals may provide a novel therapeutic strategy for gastric cancer.
Subject(s)
Angiotensin II/physiology , Matrix Metalloproteinase 2/analysis , STAT3 Transcription Factor/physiology , Stomach Neoplasms/metabolism , Blotting, Western , Cell Survival , Chromatin Immunoprecipitation , Electrophoretic Mobility Shift Assay , Humans , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/physiology , Tumor Cells, Cultured , Tyrphostins/pharmacology , Vascular Endothelial Growth Factor A/analysisABSTRACT
Angiotensin II (Ang II) has been reported to promote tumor progression, tumor growth and angiogenesis in many cancers. We previously observed that angiotensin II type 1 receptors (AT1R) were upregulated in human gastric cancer and may be involved in the progression of gastric cancer. We studied the effects of AT1R antagonist on angiogenesis and growth in gastric cancer xenografts to observe the mechanism action of AT1R in the gastric cancer. The results showed that the growth of gastric cancer cells was significantly suppressed by treatment with AT1R antagonist. In vivo, TCV-116, at doses of both 2 and 5 mg/kg/day, significantly suppressed tumor growth in mice (47.3 and 70.2%). Microvessel density was significantly decreased by TCV-116 (3.4 +/- 0.9 and 2.8 +/- 0.5 per field) compared with the control group (12.9 +/- 1.1 per field), and VEGF expression was significantly suppressed by AT1R antagonist. These results demonstrate that AT1R plays an important role in the progression of gastric cancer. Suppression tumor angiogenesis could be one of the mechanisms by which AT1R antagonist suppresses the growth of gastric cancer. These findings also provide a theoretical basis for the future clinical application of AT1R antagonist against gastric cancer.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Benzimidazoles/pharmacology , Biphenyl Compounds/pharmacology , Neovascularization, Pathologic/prevention & control , Stomach Neoplasms/drug therapy , Tetrazoles/pharmacology , Administration, Oral , Analysis of Variance , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Animals , Benzimidazoles/administration & dosage , Biphenyl Compounds/administration & dosage , Cell Line, Tumor , Humans , Immunohistochemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Neovascularization, Pathologic/metabolism , Statistics, Nonparametric , Stomach Neoplasms/blood supply , Stomach Neoplasms/pathology , Tetrazoles/administration & dosage , Transplantation, Heterologous , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Angiotensin II (Ang II), a main effector peptide in the renin-angiotensin system, acts as a growth-promoting and angiogenic factor via angiotensin II receptor1 (AT1R). In this study, we investigated the expression of angiotensin II type1 receptor (AT1R) in gastric cancer and the effects of Ang II on the expression of MMP2 and MMP9 in the human gastric cancer cell line MKN-28 cells. The expression of the Ang II type I receptor was examined by western and immunocytochemistry in gastric cancer cell lines and detected by real-time PCR and immunohistochemistry in normal and gastric cancer tissues. The expression of MMP2 and MMP9 were detected by real-time PCR and western after treatment with Ang II and/or AT1R antagonist. AT1R were expressed in all human gastric cancer lines and the expression of AT1R was significantly higher in cancer tissues than that in normal gastric tissues (P < 0.01). Furthermore, Ang II promoted the expression of MMP2 and MMP9 in MKN-28 cells, and the stimulatory effects of Ang II could be blocked by AT1R antagonist. These results suggest that AT1R is involved in the progression of gastric cancer and may promote the angiogenesis of gastric cancer cell line (MKN-28), and these effects may be associated with the upregulation of MMP2 and MMP9.
