Regulation of genes of the circadian clock in human colon cancer: reduced period-1 and dihydropyrimidine dehydrogenase transcription correlates in high-grade tumors.
Expression of dihydropyrimidine dehydrogenase (DPD) displays a regular daily oscillation in nonmalignant cells. In colorectal cancer cells, the expression of this 5-fluorouracil-metabolizing enzyme is decreased, but the reason remains unclear. In this study, we analyzed by real-time reverse transcription-PCR (RT-PCR) the expression of DPD and of members of the cellular oscillation machinery, period 1 (Per1), period 2 (Per2), and CLOCK, in primary colorectal tumors and normal colon mucosa derived from the same patients. Analysis of tumors according to differentiation grade revealed a 0.46-fold (P = 0.005) decrease for DPD mRNA and a 0.49-fold (P = 0.004) decrease for Per1 mRNA in undifferentiated (G3) tumors compared with paired normal mucosa. In this tumor cohort, the correlation between DPD and Per1 levels was r = 0.64, P < 0.01. In moderately differentiated (G2) colon carcinomas, reduction of DPD and Per1 mRNA levels did not reach significance, but a significant correlation between the respective mRNA levels was detectable (r = 0.54; P < 0.05). The decrease and correlation of DPD and Per1 mRNA levels were even more pronounced in female (G3) patients (DPD: female, 0.35-fold, P < 0.001 versus male, 0.58-fold, P < 0.05; and Per1: female, 0.47-fold, P < 0.01 versus male, 0.52-fold, P < 0.01). The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. Our results also revealed a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma cells.
Krugluger
Walter
W
Department of Clinical Chemistry, Hospital Rudolfstiftung, and Institute of Pathophysiology, Medical University of Vienna, Vienna, Austria. walter.krugluger@wienkav.at
Brandstaetter
Anita
A
Kállay
Enikö
E
Schueller
Johann
J
Krexner
Elisabeth
E
Kriwanek
Stefan
S
Bonner
Elisabeth
E
Cross
Heide S
HS
D056926:CLOCK Proteins; D002940:Circadian Rhythm / Q000235:genetics*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis / Q000235:genetics; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D056950:Period Circadian Proteins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic
D005136:Eye Proteins; C539022:PER1 protein, human; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D042943:Dihydrouracil Dehydrogenase (NADP); D056926:CLOCK Proteins; C538943:CLOCK protein, human