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Oxysterols induce cyclooxygenase‐2 expression in cholangiocytes: Implications for biliary tract carcinogenesis
Author(s) -
Yoon JungHwan,
Canbay Ali E.,
Werneburg Nathan W.,
Lee Sum P.,
Gores Gregory J.
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20125
Subject(s) - oxysterol , mapk/erk pathway , p38 mitogen activated protein kinases , carcinogenesis , cancer research , biliary tract , medicine , cyclooxygenase , biology , endocrinology , chemistry , microbiology and biotechnology , signal transduction , cancer , enzyme , cholesterol , biochemistry
Cyclooxygenase‐2 (COX‐2), which is expressed by cholangiocytes in biliary tract disorders, has recently been implicated in biliary tract carcinogenesis. The mechanisms responsible for this COX‐2 expression remain unclear. In human diseases, bile contains oxygenated derivatives of cholesterol (oxysterols) which possess diverse biological properties. Therefore, we determined if oxysterols modulate COX‐2 expression. The effect of an oxysterol (22(R)‐hydroxycholesterol, 22‐HC) on COX‐2 expression in KMBC cells, a human cholangiocarcinoma cell line, was examined. 22‐HC enhanced COX‐2 protein expression. This oxysterol activated p42/44 and p38 MAPK, but not JNK 1/2. A p42/44 MAPK inhibitor did not block COX‐2 induction, while p38 MAPK inhibitor effectively attenuated COX‐2 induction. Although COX‐2 mRNA levels were increased by 22‐HC, this increase was not transcriptionally regulated, as 22‐OH did not increase activity in a COX‐2 promoter gene assay. In contrast, COX‐2 mRNA stability was augmented by 22‐HC treatment, and this effect was reversed by a p38 MAPK inhibitor. In conclusion, the results demonstrate that the oxysterol 22‐HC stabilizes COX‐2 mRNA via a p38 MAPK‐dependent mechanism. This enhanced COX‐2 protein expression by oxysterols may participate in the genesis and progression of cholangiocarcinoma. (H EPATOLOGY 2004;39:732–738.)