口腔癌中Endothelin-1 對調控VEGF 所扮演的角色

Abstract

Oral squamous cell carcinoma (OSCC) is one kind of invasive malignancy arising from oral epithelial cells. According to the statistical data of the Department of Health in Taiwan, OSCC is most common cancer in head and neck and also the fifth leading cause of cancer mortality in 2010. In order to promote their own growth and dispersion, malignant tumors will secrete variant signaling molecules to recruit host blood vessels to grow into the vicinity of the tumor (so-called tumor angiogenesis). Among these signaling molecules, vascular endothelial growth factor (VEGF) is the most important and usually overexpresses in head and neck squamous cell carcinoma. In OSCC, VEGF highly correlates with microvessel density (MVD) of oral cancer micro-environment, and negatively correlates with the survival rates of OSCC patients. Besides, endothelin-1 (ET-1) composed of 21 amino acids plays an important role in tumor growth, metastases, and angiogenesis. Furthermore, it is proved that ET-1 released by tumors would activate endothelin A receptor (ETAR) of the tumor cells and induce VEGF expression in ovarian. Moreover, studies indicated that the expression of ET-1 is increased in OSCC cell lines. However, the relationship between ET-1 and VEGF in OSCC is still not clear. Therefore, in this study we want to testify that whether ET-1 will modulate the expression of VEGF in OSCC via ETAR, and also confirm this phenomenon in clinical samples at the same time. Firstly, we find the significant correlation between ET-1 and VEGF expressions with immunohistochemical stain in clinical OSCC samples. In survival analysis, the patients with high VEGF expressions, instead of ET-1, have lower survival rates, and there is a statistical significance. In the studies of OSCC cell lines, after ET-1 stimulated, the expression of VEGF was increased in OSCC cells, and was inhibited by ETAR antagonist (BQ-123). This phenomenon indicated that ET-1 would induce the expression of VEGF via ETAR in OSCC, and the basal expressions of ET-1 and VEGF would regulate this result. On the other hand, VEGF expression did not inhibit completely by ETAR antagonist when compared with the control group or the group with BQ-123 only. We speculated that ET-1 might be a strong agonist, or the other receptor of ET-1, endothelin B receptor (ETBR), had the similar function as ETAR did. However, the expression of VEGF is regulated by many factors, so therefore we need to study the underlying mechanism of carcinogenesis. Finally, the basal expressions of mRNA of ET-1 and VEGF were varied between selected nine OSCC cell lines. There was a positive correlation between ET-1 and VEGF when we omitted OEC-M1 and OC-2 which expressed great levels of VEGF mRNA. This result matched the finding of clinical samples. According to the experimental results, ETAR antagonist will inhibit the expression of VEGF in OSCC; however, it still further studies whether ETAR antagonist can become a candidate of the anti-cancer drug.