Nicotine induced the expression of Cyr61 in oral epithelial cells
Date Issued
2008
Date
2008
Author(s)
Hsieh, Chia-Ying
Abstract
According to the top 10 causes of death in Taiwan published by the department of health, cancer has been the top 1 for 21 years. The occurrence rate and mortality rate of oral cancer is the top four and top five of the ten most common cancers of Taiwanese male, respectively. Among oral caner, squamous cell carcinoma (SCC) is the most common one. Many researches had proved that the carcinogen in tobacco is one of the most important causes of oral cancer, and nicotine is one of the main components of tobacco. Nicotine can alter the cell functions, such like the growth and adhesion of the cells, and the production of matrix protein. Cyr61 is a member of the CCN family, which involves the regulation of cell adhesion, migration, proliferation, differentiation, apoptosis and angiogenesis, and was reported to be related to the occurrence of cancer. Previous study of our laboratory found that there was much higher expression of Cyr61 in the cancerous tissue of oral cancer patients than that of normal tissue; Cyr61 overexpressing transgenic SCID mice had larger tumor and improvement of angiogenesis. These data indicated that Cyr61 is closely related to oral cancer. The main purpose of this research is to find out whether nicotine can induce the expression of Cyr61 in the oral epithelial cells and to investigate the signaling pathway. We found that 10μM nicotine could induce the protein expression of the normal epithelial cell line S-G cells and the cancerous cell lines Ca9-22 and KB. The expression of protein and mRNA of Cyr61 in KB was elevated after treatment of 0.5 hour, and reached a high after 2 and 0.5 hours, and returned to the origin after 8 and 2 hours, respectively. Pre-treatment of KB cells with the inhibitor of α3、α7 and α9 nicotinic acetylcholine receptor (nAchR) d-tubocurarine and the inhibitor of α7 nAchR MG 624 but not the inhibitor of α3 nAchR macamylamine and that of α9 nAchR strychnine reversed the activation of Cyr61 expression; treatment of α7 nAchR agonist choline alone also stimulated Cyr61 expression, indicated that nicotine induced Cyr61 expression through α7-containing but not α3- and α9- containing nAchR. The inhibitor of cholinergic receptor atropine but not the inhibitor of M2 and M3 muscarinic acetylcholine receptor (mAchR) 4-DAMP and gallamine could suppress Cyr61 expression, proved that the activation was not through the mAchR. The expression of Cyr61 could be blocked by pre-treatment of p38 MAPK inhibitor SB203580 showed that p38 probably participated in the activation pathway, and other specific inhibitors had ruled out the possibility of involvement of MSK1, PKA and the Rho A GTPase family. This article showed that nicotine could induce the expression of Cyr61 through p38 MAPK pathway for the first time, and the signaling pathway can be the target of treating the oral cancer caused by smoking.
Subjects
oral cancer
oral epithelial cells
nicotine
SDGs
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