Association between adenomatosis polyposis coli functional status and microsomal prostaglandin E synthase-1 expression in colorectal cancer
✍ Scribed by Nils Elander; Jianlin Zhou; Jonas Ungerbäck; Jan Dimberg; Peter Söderkvist
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 222 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0899-1987
- DOI
- 10.1002/mc.20500
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✦ Synopsis
Bioactive metabolites downstream of cyclooxygenase-2 (COX-2) generated prostaglandin H 2 (PGH 2 ), in particular prostaglandin E 2 (PGE 2 ), are thought to play critical roles during the development of colorectal tumors. Previous reports reveal that defects of the tumor suppressor adenomatosis polyposis coli (APC) contribute to COX-2 upregulation in colon tumor cells. We investigated whether a similar relation was present between APC functional status and the expression of microsomal prostaglandin E synthase-1 (mPGES-1), which acts downstream of COX-2 and catalyses the terminal conversion of PGH 2 into PGE 2 . Surprisingly, mPGES-1 mRNA and protein levels were upregulated upon induction of a wild type-APC carrying vector in HT29 colon cancer cells, and downregulated following siRNA silencing of APC in HCT-116 cells. mPGES-1 was overall enhanced in human colorectal tumor specimens versus corresponding non-tumor mucosa and, in accordance with data on HT29 and HCT116 cells, higher levels of mPGES-1 were observed among tumors carrying wild type versus mutant APC. RNAi silencing of b-catenin and luciferase assays regarding the mPGES-1 promoter region did not reveal a role for APC or b-catenin/Tcf in controlling mPGES-1 gene transcription. However, RNA degradation assays in HT29 cells revealed a suppressed degradation of mPGES-1 in the presence of wild type APC, implying that mPGES-1 mRNA is stabilized in the APC wild type state. Collectively, we demonstrate a novel association between APC functional status and mPGES-1 expression in colorectal tumor cells, being most likely related to reduced mPGES-1 mRNA degradation rate in the APC wild type state.