Korean J Urol.  2006 Mar;47(3):310-315. 10.4111/kju.2006.47.3.310.

The Effect of Cyclooxygenase-2 Inhibitor on the Gene Expression Profile of N-butyl-N-(4-hydroxybutyl) nitrosamine-induced Rat Urinary Bladder Cancer

• Kwon SM
• Oh HY
• Lee EJ
• Kim SI
• Hong SJ

• KMID: 2294180
• DOI: http://doi.org/10.4111/kju.2006.47.3.310

Abstract

PURPOSE: Cyclooxygenase (COX)-2 plays an important role in promoting cancer cell proliferation and angiogenesis in human bladder cancer. In this study, we investigated the antitumor or antiangiogenic effects of selective COX-2 inhibitor on N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder tumorigenesis.
MATERIALS AND METHODS
Forty male Fischer 344 rats (control) were given only 0.05% BBN, while 40 rats (experimental) were administered 1,500mg/ kg celecoxib once daily and this treatment started from 1 week before their BBN treatment. Ten rats from the control groups and the experimental groups were then sacrificed at 4, 12, 16 and 24 weeks after BBN treatment. We observed all the bladders macroscopically as well as microscopically, and we measured the COX-2 expression in the bladder tissues. Utilizing a cDNA microarray, we analyzed the significant differences of gene expression between the 12 week-control group and the 12 week-experimental group.
RESULTS
The incidence of tumor was lower in the experimental group than in the control group from week 12 to week 24. The COX-2 expressions were more significantly decreased via the BBN induction (p<0.05) in the experimental groups than in the control groups after 4 weeks. For the 12 week-experimental group, there were 15 genes altered by the administration of selective COX-2 inhibitor, and the selective COX-2 inhibitor especially regulated transgelin, membrane metallo endopeptidase and apolipoprotein E of these 15 genes to prevent the incidence of bladder tumor.
CONCLUSIONS
Selective COX-2 inhibitor has an inhibitory effect on BBN-induced rat bladder tumorigenesis. In the pre-neoplastic phase, selective COX-2 inhibitor regulates transgelin, membrane metallo endopeptidase and apolipoprotein E to prevent the incidence of bladder tumor.

Keyword

Butylhydroxybutylnitrosamine; Bladder cancer; Angiogenic factor; cDNA microarray; Rats

MeSH Terms

Angiogenesis Inducing Agents
Animals
Apolipoproteins
Butylhydroxybutylnitrosamine
Carcinogenesis
Cell Proliferation
Cyclooxygenase 2*
Gene Expression*
Humans
Incidence
Male
Neprilysin
Oligonucleotide Array Sequence Analysis
Prostaglandin-Endoperoxide Synthases
Rats*
Transcriptome*
Urinary Bladder Neoplasms*
Urinary Bladder*
Celecoxib
Angiogenesis Inducing Agents
Apolipoproteins
Butylhydroxybutylnitrosamine
Cyclooxygenase 2
Neprilysin
Prostaglandin-Endoperoxide Synthases

Figure

• 

  Fig. 1 Altered genes by administering selective COX-2 inhibitor. Fifteen genes are differentially expressed by administering selective COX-2 inhibitor. The ratio of the median, mean and log of Cy5/Cy3. EST and transgelin are up-regulated by the selective COX-2 inhibitor on the results of triplicate experiments, and mme and Apo-E are down-regulated. COX-2: cyclooxygenase-2, mme: membrane metallo endopeptidase, Apo-E: apoplipoprotein-E.

• 

  Fig. 2 The transgelin, Apo-E and mme expressions by cDNA microarray and RT-PCR. In week 12, the transgelin, Apo-E and mme expressions of the bladder tissues on cDNA microarray are similar to results obtained on RT-PCR. (A) Electrophoresis on 2% agarose gel after RT-PCR. (B, C, D) Comparison between the cDNA microarray and RT-PCR for the transgelin, Apo-E and mme expression. The relative intensity is the ratio of each gene's intensity to the β-actin intensity. RT-PCR: reverse transcriptase-polymerase chain reaction, Apo-E: apolipoprotein E, Mme: membrane metallo endopeptidase.

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