Bile acid promotes the proliferation of squamous cell carcinoma of the esophagus, independent of its inducing COX-2 expression.
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).


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.
Nishioka
Kiyonori
K
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, 565-0871, Japan.
Doki
Yuichiro
Y
Miyata
Hiroshi
H
Tamura
Shigeyuki
S
Yasuda
Takushi
T
Kimura
Yutaka
Y
Kishi
Kentaro
K
Yoshida
Koji
K
Fujiwara
Yoshiyuki
Y
Yano
Masahiko
M
Monden
Morito
M
D001647:Bile Acids and Salts / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004938:Esophageal Neoplasms; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007700:Kinetics
D001647:Bile Acids and Salts; D051546:Cyclooxygenase 2