Celecoxib activates Stat5 and restores or increases the expression of growth hormone-regulated genes in hepatocarcinogenesis.
We have previously evaluated the chemopreventive effect of celecoxib on preneoplastic lesions in rat liver. However, though the effects of celecoxib have been tested in a variety of carcinomas, there has not been a study on the modulation of gene expression in response to this drug. Here, we evaluated the effect of celecoxib on the gene expression profile associated with hepatocarcinogenesis. Male Sprague-Dawley rats underwent the modified resistant hepatocyte model and were fed a diet containing 1500 ppm of celecoxib. Gene expression profiles were evaluated using DNA microarrays and further validations were performed using quantitative PCR, western blotting and immunohistochemical staining. Celecoxib modulated the expression of 46 genes, and those regulated by growth hormone were selected for further analysis. Celecoxib significantly upregulated the expression of the Cyp2b1/2, Cyp3a1, and alpha2-urinary globulin (alpha2uG) genes and restored the expression of Cyp2b3 to normal. The protein expression of Cyp2b1/2 was increased, but the expressions of Cyp3a1 and alpha2uG were only restored to normal levels. The increased Cyp2b1/2 expression in response to celecoxib was mainly confined to preneoplastic lesions. A search for the upstream mediator of these genetic alterations found that carcinogenesis inactivated by 87% the signal transducer and activator of transcription 5 (Stat5), a transcription factor that is activated by growth hormone signaling, but celecoxib treatment restored its activation. In conclusion, these results suggest that celecoxib exerts anticancer effects on altered hepatic cells by restoring mRNA and the protein expression levels of specific genes, in part through the reactivation of Stat5.
Department of Cell Biology, Center of Research and Advanced Studies of the National Polytechnic Institute, San Pedro Zacatenco, Mexico.
Jaime
J
Arellanes-Robledo
Martha Estela
ME
Salcido-Neyoy
Adriana
A
Márquez-Quiñones
Rebeca
R
García-Román
Olga
O
Beltrán-Ramírez
Véronique
V
Le Berre
Sergueï
S
Sokol
Jean Marie
JM
François
Saúl
S
Villa-Treviño
D000510:Alpha-Globulins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D000068579:Celecoxib; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D013006:Growth Hormone / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
D000510:Alpha-Globulins; D000970:Antineoplastic Agents; D011720:Pyrazoles; D050799:STAT5 Transcription Factor; D013449:Sulfonamides; C013803:alpha 2u globulin; D013006:Growth Hormone; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C089142:Cyp2b3 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; C025619:steroid 16-beta-hydroxylase; D000068579:Celecoxib