Association between adenomatosis polyposis coli functional status and microsomal prostaglandin E synthase-1 expression in colorectal cancer.
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 beta-catenin and luciferase assays regarding the mPGES-1 promoter region did not reveal a role for APC or beta-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.
Elander
Nils
N
Faculty of Health Sciences, Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Sweden.
Zhou
Jianlin
J
Ungerbäck
Jonas
J
Dimberg
Jan
J
Söderkvist
Peter
P
D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D020868:Gene Silencing; D017491:Genes, APC; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases