Bile acid promotes the proliferation of squamous cell carcinoma of the esophagus, independent of its inducing COX-2 expression |
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Authors: | Nishioka Kiyonori Doki Yuichiro Miyata Hiroshi Tamura Shigeyuki Yasuda Takushi Kimura Yutaka Kishi Kentaro Yoshida Koji Fujiwara Yoshiyuki Yano Masahiko Monden Morito |
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Institution: | Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, 565-0871, Japan. |
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Abstract: | BACKGROUND: We have reported G1 progression and cyclooxygenase-2 (COX-2) induction during carcinogenesis of the squamous epithelium of the esophagus. As bile acid induces COX-2 expression and promotes carcinogenesis in the digestive tract, we investigated the effect of bile acid on the proliferation of squamous cell carcinoma of the esophagus (ESCC). MATERIALS AND METHODS: MTT assay, Western blot analysis of COX-2 and cell cycle-related molecules in the G1 phase (Rb, CDC25A, cyclin D1), and CDK2 kinase assay were performed on chenodeoxycholic acid (CDCA) exposure to ESCC cell lines (TE2R, TE3, TE13, TE15). RESULTS: In the presence of gradient bile acid concentration (up to 100 microm), growth of ESCC cell lines was stimulated at a low concentration (maximally at 20-30 microm), but suppressed at a higher concentration. Only a low dose of bile acid induced the expression of cyclin D1 and CDC25A and showed high Rb phosphorylation and high CDK2 kinase activity. In contrast, bile acid progressively induced COX-2 expression in a dose-dependent manner, regardless of its biphasic effects on cell proliferation, and a COX-2 specific inhibitor (JTE-522) did not suppress growth stimulation by a low dose of bile acid. CONCLUSIONS: Bile acid at a low dose stimulates the proliferation of ESCC by inducing G1-regulating molecules. However, COX-2 expression, which is also induced by bile acid, does not affect cell proliferation. Further work is needed to elucidate its role in carcinogenesis. |
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Keywords: | bile acid ESCC proliferation duodeno-gastro-esophageal reflux COX-2 |
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