Colorectal cancer is the result of progressive transformation of colonic epithelium into neoplastic tissue. A cascade of genetic and/or epigenetic events is involved in the process of cancer transformation. Neoplastic conditions lead to hyperproliferation of colonic crypts accompanied by delay or inhibition in cellular differentiation and apoptosis and progresses through a series of stages through formation of polyps that can be transformed into malignant cancer. Recent epidemiologic studies have revealed that disturbances of circadian homeostasis are associated with an increased risk of developing cancer. Many experiments have also shown that various genes involved in cell proliferation including regulators of the cell cycle, components of cell cycle checkpoints and growth factors are under transcriptional control of the circadian clock. In our previous experiments we described the presence of circadian clock in colonocytes. Moreover, we described circadian rhythmicity in colon electrolyte transport and cell cycle regulator Wee1. Taken together, these results further supportthe existence of functional intestinal circadian clock. In addition, we have shown that disruption of circadian regulation in colonic neoplastic tissue in murine model of colorectal cancer is associated with inflammatory bowel disease.
Understanding the circadian regulation of cell division and proliferation in colon is of utmost importance because there are numerous situations in modern lifestyle associated with repeated exposure to abnormal light/dark regimes (shift work), which might lead to increased incidence of tumors in various tissues, including gastrointestinal tract
The scope of this project is
(1) to ascertain whether disruption of circadian rhythms is linked to tumorigenesis in colon in vivo,
(2) to specify whether the circadian clock and the cell cycle are desynchronized in colorectal cancer and
(3) to determine whether deficiency in colonic circadian clock leads to local changes in glucocorticoid signaling and multidrug resistance.
The project is investigated in cooperation with the Department of Neurohumoral Regulations of the
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Moravec M, Švec J, Ergang P, Mandys V, Řeháková L, Zádorová Z, Hajer J, Kment M, Pácha J. Expression of 11β-hydroxysteroid dehydrogenase type 2 is deregulated in colon carcinoma. Histol Histopathol 29:489-96, 2014
Soták M, Polidarová L, Ergang P, Sumová A, Pácha J. An association between clock genes and clock-controlled cell cycle genes in murine colorectal tumors. Int J Cancer 132:1032-41. 2013
Polidarová L, Sládek M, Soták M, Pácha J, Sumová A. Hepatic, duodenal, and colonic circadian clocks differ in their persistence under conditions of constant light and in their entrainment by restricted feeding. Chronobiol Int 28:204-15, 2011