Clinicopathological significance of circadian rhythm-related gene expression levels in patients with epithelial ovarian cancer.
OBJECTIVE
Recent studies implicate circadian genes in the regulation of cell cycle, apoptosis, and cell proliferation at a molecular level. These genesey affect cancer incidence, prognosis, and chemosensitivity. In this study, we measured the expression levels of clock genes and correlated their expression levels with clinicopathological parameters in epithelial ovarian cancer.


METHODS
The expression levels of core clock genes, per1, per2, per3, cry1, cry2, Bmal1, clock, and CKIepsilon were quantified by real-time quantitative Reverse transcription-polymerase chain reaction in 83 ovarian cancer tissues and 11 normal ovarian tissues.


RESULTS
The expression levels of per1, per2, cry2, clock, CKIepsilon in ovarian cancers were significantly lower than those in normal ovaries. In contrast, cry1 expression was highest among the eight examined clock genes, followed by per3 and Bmal1. Cry1 expression was much higher in cancer than that in normal ovaries. Localized circadian gene expression was determined in cancer cells by in situ hybridization analysis. Cry1 expression was significantly reduced in mucinous and grade 3 tumors. Bmal1 expression was also significantly reduced in mucinous adenocarcinomas as compared to other histologies. In a multivariate analysis, the combination of low cry1 expression and low Bmal1 expression was an independent prognostic factor, as well as stage and histological subtype.


CONCLUSIONS
The antiphase expression of cry1 and Bmal1 may be preserved in ovarian cancers. The combination of cry1 and Bmal1 expression might become a possible prognostic marker in epithelial ovarian cancer.
Tokunaga
Hideki
H
Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Takebayashi
Yuji
Y
Utsunomiya
Hiroki
H
Akahira
Jun-Ichi
J
Higashimoto
Masashi
M
Mashiko
Miyuki
M
Ito
Kiyoshi
K
Niikura
Hitoshi
H
Takenoshita
Sei-Ichi
S
Yaegashi
Nobuo
N
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics*; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm