Colorectal cancer represents a leading cause of cancer death. MicroRNAs (miRNAs) are small non-coding RNA molecules that have been extensively studied in tumours, since changes in their levels can reveal patient prognosis. Cancer progression is also influenced by the circadian system whose functioning is based on the rhythmic expression of clock genes. Therefore, we performed macroarray screening of tumour and adjacent tissues in patients undergoing surgery for colorectal carcinoma. We identified 17 miRNAs showing expression that was more than 100 times higher in tumour tissue compared to adjacent tissue. From in silico analysis, miR-34a-5p was selected as showing a computer-predicted interaction with PER2. Real-time PCR revealed a negative correlation between expression of PER2 mRNA and miR-34a in patients with more advanced cancer stage. Expression of miR-34a was up-regulated in cancer tissue compared to adjacent tissue. High miR-34a expression was associated with better survival of patients. miR-34a showed lower expression levels in male patients with lymph node involvement, and a trend towards decreased expression in male patients with distant metastases. Male patients, but not female patients, with high expression of miR-34a and who were free of distant metastases and/or lymph node involvement showed better survival. Therefore, we proposed that expression of miR-34a was regulated in a sex-dependent manner and could be considered a marker of prognosis in earlier cancer stages in male patients.
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.
miRNAs are small regulatory RNA molecules involved in post-transcriptional gene silencing. Their biosynthesis results in the formation of duplex consisting of a leading and a passenger strand of mature miRNA. The leading strand exhibits the main activity but recent findings indicate a certain role of the passenger strand as well. Deregulated levels of miRNA were found in many types of cancers including colorectal cancer. miR-21 and miR-16 were indicated as possible markers of colorectal cancer, however, small attention to gender differences in their expression was paid so far. Therefore, the aim of our study was to investigate the expression of miR-21-5p, miR-21-3p, miR-16-5p and miR-16-3p in human colorectal cancer tissue and compare it to the adjacent tissues taken during surgery in men and women separately. Our results showed an up-regulation of all measured miRNAs in tumor tissue compared to adjacent tissues. As expected, tumors and adjacent tissues exhibited a significantly higher expression of leading miRNAs compared to passenger strand of miR-21 and miR-16. The expression of leading and passenger strand of miR-21 and miR-16 positively correlated exhibiting the highest correlation coefficient in the distal tissue. The expression pattern showed gender-dependent differences, with higher levels of miRNA in men than in women. Our findings indicate a gender-related expression pattern of miRNA, which should be considered as an important factor in generating new prognostic or diagnostic biomarkers.
Colorectal cancer (CRC) exhibits differences in its features depending on the location of the tumor. The role of the circadian system in carcinogenesis is accepted, and many studies report different clock gene expression in tumors compared to healthy tissue. However, little attention is given to the changes in clock genes in tumors arising from various locations across the colon and rectum. The aim of our study was to investigate the expression of the clock genes cry1 and cry2 in human CRC tissue and tissue adjacent to colorectal tumors in a cohort of 64 patients by real time PCR. Expression of cry1 in the entire patient cohort was higher in tumors compared to adjacent tissues in the right-sided colon but not in the left-sided colorectum. Difference in cry1 expression between tumor and adjacent tissue in the right-sided colon was preserved in women and a trend was observed in men. Higher expression of cry1 in the right-sided colon tumor tissue was associated with worse survival in women and the expression of cry1 in the left-sided colorectum was significantly higher in the adjacent tissue compared to tumor in men but not in women. Expression of cry2 was lower in the tumor than in adjacent tissue in both the right and left-sided colorectum. This trend was generally preserved, but the difference reached significance level only in the male left-sided colon, and cry2 expression in the tumor tissue significantly correlated with location of the tumor in men with grade 2 cancer. Finally, we detected significant correlation between tumor location and cry1 expression in the adjacent tissue and the combined results establish that tumor influence on adjacent tissue is dependent on tumor location. Changed clock gene expression should therefore be considered in specific CRC patient sub-groups.
The effects of food reward on circadian system function were investigated in the hypothalamic nuclei, prefrontal cortex and liver. Food rewards of small hedonic and caloric value were provided for 16 days 3 h after light phase onset to male Wistar rats. The daily pattern of locomotor activity was monitored. Gene expression profiling performed in the dorsomedial hypothalamus (DMH) and liver at the time of reward delivery indicated transcriptional factors egr1 and npas2 as possible mediators of food reward effects. Candidate genes were measured in the suprachiasmatic nuclei (SCN), DMH, arcuate nucleus (ARC), prefrontal cortex (PFC) and liver along with per2 expression. A daily pattern in glycemia and per2 expression in the SCN was emphasized by food reward. The expression of egr1 was rhythmic in the SCN, DMH, PFC and liver and food reward weakened or diminished this rhythm. The expression of npas2 was rhythmic in all tissues except for the PFC where food reward induced rhythm in npas2 expression. Food reward induced npas2 and egr1 expression in the DMH at the time of reward delivery. We suppose that the DMH and PFC participate in the adjustment of the circadian system to utilize food reward-induced input via egr1 and npas2 expression.
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