Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line |
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Authors: | Yoon Jung-Hwan Higuchi Hajime Werneburg Nathan W Kaufmann Scott H Gores Gregory J |
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Institution: | Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA. |
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Abstract: | BACKGROUND & AIMS: Although bile acids have been implicated in colon cancer development, their role in biliary tract carcinogenesis remains unexplored. Because receptor tyrosine kinases and cyclooxygenase (COX)-2 have been implicated in carcinogenesis, we examined the hypothesis that bile acids modulate these enzymes in KMBC cells, a human cholangiocarcinoma cell line. METHODS: The effect of bile acids on epidermal growth factor receptor (EGFR) stimulation, mitogen-activated protein kinase (MAPK) activation, and COX-2 expression was evaluated. RESULTS: Bile acids both induced EGFR phosphorylation and enhanced COX-2 protein expression. Bile acid-induced EGFR phosphorylation was associated with subsequent activation of MAPK p42/44, p38, and c-Jun-N-terminal kinase (JNK). The MAPK inhibitors, PD098059 for MAP or extracellular signal-regulated kinase 1, SB203580 for p38, and BAY 37-9751 for Raf-1, blocked COX-2 induction by bile acids. However, inhibition of JNK activity did not block bile acid-mediated COX-2 induction. CONCLUSIONS: The results show that EGFR is activated by bile acids and functions to induce COX-2 expression by an MAPK cascade. This induction of COX-2 may participate in the genesis and progression of cholangiocarcinomas. |
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Keywords: | COX cyclooxygenase DC deoxycholate ON dominant negative EGFR epidermal growth factor receptor GCDC glycochenodeoxycholate GDC glycodeoxycholate JNK c-Jun-N-terminal kinase MAPK mitogen-activated protein kinase MEK MAP or extracellular signal-regulated kinase MOI multiplicity of infection TAK1 transforming growth factor β-activated kinase 1 TCDC taurochenodeoxycholate TDC taurodeoxycholate |
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