Oxysterols Induce Cyclooxygenase-2 Expression in Cholangiocytes: Implications for Biliary Tract Carcinogenesis

Jung Hwan Yoon, Ali E. Canbay, Nathan W. Werneburg, Sum P. Lee, Gregory James Gores

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)732-738
Number of pages7
JournalHepatology
Volume39
Issue number3
DOIs
StatePublished - Mar 2004

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Biliary Tract
Cyclooxygenase 2
Carcinogenesis
Cholesterol
p38 Mitogen-Activated Protein Kinases
Cholangiocarcinoma
Mitogen-Activated Protein Kinase 1
Oxysterols
Messenger RNA
RNA Stability
Bile
Proteins
22-hydroxycholesterol

ASJC Scopus subject areas

  • Hepatology

Cite this

Oxysterols Induce Cyclooxygenase-2 Expression in Cholangiocytes : Implications for Biliary Tract Carcinogenesis. / Yoon, Jung Hwan; Canbay, Ali E.; Werneburg, Nathan W.; Lee, Sum P.; Gores, Gregory James.

In: Hepatology, Vol. 39, No. 3, 03.2004, p. 732-738.

Research output: Contribution to journalArticle

Yoon, Jung Hwan ; Canbay, Ali E. ; Werneburg, Nathan W. ; Lee, Sum P. ; Gores, Gregory James. / Oxysterols Induce Cyclooxygenase-2 Expression in Cholangiocytes : Implications for Biliary Tract Carcinogenesis. In: Hepatology. 2004 ; Vol. 39, No. 3. pp. 732-738.
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