Document Type

Article

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Prostaglandin E2 (PGE2) is reported to play an important role in tumor development. We explored the differential expression of genes governing production of, and response to, PGE2 during development of invasive bladder cancer. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) or vehicle-treated mice (n = 4–5) were euthanized after 4–8 weeks (period 1, P1), 12–16 weeks (P2), and 20–23 weeks (P3). Half of each bladder was analyzed histologically and the other half extracted for mRNA analysis by quantitative real-time PCR. Bladders from BBN-treated mice showed progression from submucosal inflammation (P1) to squamous metaplasia/focal CIS (P2) to poorly differentiated, invasive cancer (P3). mRNA levels for the inducible cyclooxygenase, COX-2, were elevated three to fourfold at all time points in BBN-treated mice compared to controls. In contrast, mRNA levels for constitutive COX-1 and cytosolic phospholipase A2 (cPLA2), which releases substrate for COX, were either unchanged or decreased in BBN-treated mice relative to controls. Downstream of COX, mRNA levels of membrane-bound PGE2 synthase (mPGES-1) were increased 1.7-fold at P1 in BBN bladders but returned to control levels at P2 and P3. mRNA levels for 15-prostaglandin dehydrogenase (PGDH), which inactivates PGE2, were reduced 50–80% in BBN-treated bladders at all time points. mRNA levels for EP2R and EP4R, receptors for PGE2, were two to threefold increased at P1, but returned to control levels or below at P3. Hence, increased COX-2 and decreased PDGH expression occurred throughout tumor development, while mPGES-1, EP2R and EP4R were elevated only before development of invasive cancer. We compared expression of these genes in the malignant human urothelial cell lines, HTB-5 and HT-1376, with expression in a benign urothelial cell line, UROtsa. Neither malignant cell line reproduced the complete in vivo pattern, relative to benign cells, but each showed abnormal basal expression of several of the genes downstream of COX-2, but not COX-2 itself. We conclude that components involved in PGE2 synthesis and activity are differentially regulated during bladder tumor development and the therapeutic efficacy of targeting the various components may vary with stage of tumor development.

Comments

Author manuscript; available in PMC 2010 January 1. Published in final edited form as: Prostaglandins Other Lipid Mediat. 2009 January; 88(1-2): 36–41. Published online 2008 September 12. doi: 10.1016/j.prostaglandins.2008.09.003. PMCID: PMC2615552 NIHMSID: NIHMS84408

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