Sex-dependent correlation between survival and expression of genes related to the circadian oscillator in patients with colorectal cancer

Abstract

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.

Sex-Dependent Regulation of Estrogen Receptor β in Human Colorectal Cancer Tissue and its Relationship With Clock Genes and VEGF-A Expression

“…In males, the expression of ERβ mRNA in cancer tissue shows a similar decrease in CRC compared with healthy tissues in all stages of disease. This finding is in agreement with our observation that ERβ mRNA expression correlates with survival in females but not in males (Hasakova et al 2018).…”

“…Recent findings are in accordance with a previous report of sexual dimorphism in gene expression in CRC. Core clock genes PER2 and CRY2 exerted a more pronounced decrease in cancer tissue than in healthy tissues in males compared with females (Hasakova et al 2018). Similarly, expression of miRNAs miR-16 and miR-21 showed sex-dependent differences in expression in cancer compared with healthy tissue (Hasakova et al 2017).…”

“…PER2 (NM_022817.1) sense 5'-AATGCCGATATGTTTGCGGT-3', antisense 5'-GCATCGCTGAAGGCATCTCT-3'; CRY1 (NM_004075.4) sense 5'-CCGTCTGTTTGTGATTCGTG-3', antisense 5'-AAGTTAGAGGCGGTTGTCCA-3'; CRY2 (NM_001127457.2) sense 5'-GGAGGCTGGTGTGGAAGTAG-3', antisense 5'-CGTAGGTCTCGTCGTGGTTC-3'; VEGF-A (NM_001171623.1) sense 5'-AGAAGGAGGAGGGCAGAATC-3', antisense 5'-CATCAGGGGCACACAGGAT-3'; ERβ (NM_001437.2) sense 5'-TGAGGGGAAATGCGTAGAAGG-3', antisense 5'-CGTTCAGCAAGTGAGCCAG-3'; U6 (NR_004394.1) sense 5'-GCTTCGGCAGCACATATACTAA-3', antisense 5'-AAAATATGGAACGCTTCACGA-3' (Zeman et al 2008, Hasakova et al 2018.…”

“…ERβ mRNA expression has been previously shown to exhibit a sex-dependent association with patient survival (Hasakova et al 2018). A sex-dependent role of the circadian system in tumorigenesis was demonstrated in a study pointing out different survival rates in males and females depending on administration of chronomodulated chemotherapy (Giacchetti et al 2012).…”

Osteosarcoma journey over two decades in India: Small steps, big changes

“…39 There is a possible link between cancer outcomes, circadian system, and varied genderspecific clock-controlled gene expression, which explains better survival in females. 40 These new predictors are thought provoking and merit exploration for reproducibility. If reproducible, they can be used to create a "prognostic score" in osteosarcoma, which may be utilized to individualize therapy in an early phase.…”