Epigenetic changes of tumor suppressor genes, P15, P16, VHL and P53 in oral cancer

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Title:	Epigenetic changes of tumor suppressor genes, P15, P16, VHL and P53 in oral cancer
Authors:	Yeh, KT;Chang, JG;Lin, TH;Wang, YF;Tien, N;Chang, JY;Chen, JC;Shih, MC
Contributors:	附設醫院醫研部;China Med Coll Hosp, Dept Mol Med, Taichung, Taiwan;China Med Coll Hosp, Dept Lab Med, Taichung, Taiwan;Changhua Christian Hosp, Dept Pathol, Changhua, Taiwan
Date:	2003
Issue Date:	2010-09-24 14:58:46 (UTC+8)
Publisher:	PROFESSOR D A SPANDIDOS
Abstract:	Endothelin-1 (ET-1) has been implicated in fibroblast proliferation. However, the mechanism involving ET-1 is not clear. The present study was performed to examine the role of endogenous ET-1 in ET-1-stimulated fibroblast proliferation and to investigate the regulatory mechanism of ET-1-induced ET-1 gene expression in cardiac fibroblasts. Both ETA receptor antagonist [(hexahydro-1H-azepinyl)carbonyl-Leu-D-Trp-D-OH (BQ485)] and endothelin-converting enzyme inhibitor (phosphoramidon) inhibited the increased DNA synthesis caused by ET-1. ET-1 gene was induced by ET-1, as revealed with Northern blotting and ET-1 promoter activity assay. ET-1 increased intracellular reactive oxygen species (ROS), which were significantly inhibited by BQ485 and antioxidants. Antioxidants suppressed ET-1 gene expression and DNA synthesis stimulated by ET-1. ET-1 activated mitogen-activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase, which were significantly inhibited by antioxidants. Only ERK inhibitor U0126 could inhibit ET-1-induced transcription of the ET-1 gene. Co-transfection of dominant-negative mutant of Ras, Raf, and MEK1 decreased the ET-1-induced increase in ET-1 transcription, suggesting that the Ras-Raf-ERK pathway is required for ET-1 action. Truncation and mutational analysis of the ET-1 gene promoter showed that the activator protein-1 (AP-1) binding site was an important cis-element in ET-1-induced ET-1 gene expression. Antioxidants attenuated the ET-1-stimulated AP-1 binding activity. Our data suggest that ROS were involved in ET-1-induced fibroblast proliferation and mediated ET-1 induced activation of ERK pathways, which culminated in ET-1 gene expression.
Relation:	ONCOLOGY REPORTS 10(3):659-663
Appears in Collections:	[China Medical University Hospital] Jurnal articles

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