Recent evidence supports the important role of the circadian system in
cancer progression in humans. The aim of the present study is to evaluate clock (cry1, cry2 and per2) and clock-controlled (
vascular endothelial growth factor-a,
early growth response protein 1 and
estrogen receptor β) gene expression in
colorectal cancer and adjacent tissue and identify a possible link between survival of patients and expression of above mentioned genes. The study includes 64 patients of both sexes with previously diagnosed
colorectal cancer.
RNA was extracted from the
tumor tissue and adjacent parts of the resected colon, and real-time PCR was used for detection of clock gene expression. Expression of cry2 and per2 was significantly downregulated in
tumor tissue compared to adjacent tissues. After splitting of the cohort according to sex, we detected downregulated levels of cry2 and per2 in male patients, but not in females. Splitting of male and female sub-cohorts according to presence of
metastases revealed significant donwregulation of cry2 expression in female patients without distant
metastasis. Better survival rate was associated with low expression of cry2 in female patients. Moreover, we observed an increase in cry1 expression in female patients with distant
metastases in
tumor compared to adjacent tissue. Accordingly, women with high expression of cry1 in
tumor tissue displayed worse survival, which was not observed in men. Taken together, expression of clock and clock-controlled genes in
tumors of males and females clustered according to presence of distant
metastases correlated with survival analysis. Studied clock-controlled genes also showed sex-dependent changes. Low expression of
vegf-a in
tumor correlated with better survival in men but not in women. High expression of
estrogen receptor β
mRNA was related to better survival in women but not in men. Low expression of
vegf-a, egr1 and
estrogen receptor β was associated with worse survival in women compared to men. Our data indicate sex-dependent associations between clock and clock-controlled gene expression in
cancer tissue and patient's survival prognosis.