The role of CYR61 in chemotactic migration of gastric cancer
| Autor: | Lie-Jung Chen, 陳俐蓉 |
|---|---|
| Rok vydání: | 2005 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 93 Gastric cancer is the second most common cause of cancer mortality worldwide, and development of metastasis to lymph nodes, liver, and peritoneum is responsible for the majority of cancer related death. Metastasizing cells must traverse the endothelial lining of the lymphatic or vascular systems in order to metastasize to distant sites. The previous study demonstrated that expression of CYR61 was correlated with tumor malignancy and lymph node metastasis in gastric cancer patients. It has been reported that tumor cells express specific chemokine receptors that may play roles in determining the sites of metastasis. We thus further investigated whether chemokine receptors are involved in CYR61-mediated cell migration. Messenger RNA expression of chemokine receptors was screened by RT-PCR in several stable CYR61 transfectant clones. We found that the expression of CXCR1 and CXCR2 in mRNA in AGS/CYR61 cells was strongly higher than AGS parental cells, as well as protein induction level, suggesting that CYR61 up-regulated CXCR1 and CXCR2 expression in human gastric cancer cells. Moreover, clinical study showed that CXCR1 and CXCR2 expression was tightly correlated with CYR61 in gastric tumor patients by RT-PCR and immunohistochemistry analyses. Furthermore, recombinant human IL-8 enhanced the chemotactic migration of CYR61- overexpressing gastric carcinoma cells in a time and dose dependent manner, and consistently, neutralizing antibodies to CXCR1 and CXCR2 significantly attenuated chemotactic migration of IL8-stimulated gastric cells. It was found that IL-8 is the potent chemotactic factor from conditioned medium of HUVEC that induced chemotaxis of CYR61-overexpressing cells, enhanced transendothelial migration dependent on CXCR1, CXCR2 activation in Boyden chamber assay; and active CXCR1 and CXCR2 signalings are necessary for CYR61-overexpressing gastric tumor cells to intravasate monolayer endothelium, and then enter circulating system in chicken embryo model. Our results further delineated the molecular mechanisms that CXCR1 and CXCR2 induced by CYR61 through integrin αvβ3, which is requisite for activation of c-Src and subsequent PI3k-Akt signaling pathways. Collectively, our present data suggested an association between constitutive expression of CXCR1, CXCR2 receptors and CYR61 in aggressiveness of human gastric carcinoma cells. It implicated that the IL-8 receptor system regulated chemotactic migration of gastric cancer cells, and may be involved in organ-specific gastric carcinomas metastasis and, hence, could be a potential target for therapy. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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