Correlated downregulation of estrogen receptor beta and the circadian clock gene Per1 in human colorectal cancer

Abstract

There is a growing body of evidence that disturbed circadian clock gene expression is associated with tumor development and tumor progression. Based on our initial experiments demonstrating decreased period 1 (Per1) expression in colon cancer, we evaluated clock gene and estrogen receptor (ER) alpha/beta expression in colon cancer cells of primary colorectal tumors and adjacent normal colon mucosa (NM) by real-time RT-PCR. Analysis of gene expression in G(2) and G(3) colorectal tumors revealed a decrease of Per1 mRNA compared with paired NM (G(2): 0.52-fold; P = n.s. and G(3): 0.48-fold; P = 0.03). A significant gender specific difference of Per1 expression was observed in G(2) tumors as compared with NM (female: 0.38-fold; P = 0.004 vs. male: 0.73-fold; P = n.s.). Expression of CLOCK was significantly elevated in G(2) tumors of male patients (1.63-fold, P = 0.01). The expression of ER-beta was significantly decreased in G(2) and G(3) tumors (G(2): 0.32-fold; P = 0.003 and 0.27; P = 0.001). No significant gender specific differences of ER-beta reduction in tumors were observed. A significant correlation between the decrease of Per1 and ER-beta in colorectal tumors (r = 0.61; P < 0.001) was found. No changes in gene expression were detected for ER-alpha and Per2. Our data demonstrate a correlated decrease of Per1 and ER-beta in colorectal tumors, mediated probably by epigenetic mechanisms. The observed gender differences in the expression of CLOCK and Per1 in G(2) tumors might suggest a gender-specific, distinctive role of the cellular clock in colorectal tumorigenesis.

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

“…Other groups have shown that ERbKO mice are more susceptible to inflammation-associated colon cancer than the WT mice (Saleiro et al 2012). Clinical and experimental models of colonic carcinogenesis have suggested that the protein expression of ERb decreases as the tissues progress from a normal colonic epithelial to a malignant state (Konstantinopoulos et al 2003, Castiglione et al 2008, Di Leo et al 2008, Mostafaie et al 2009). In fact, humans with colon tumors not expressing ERb are likely to be in more advanced stages of cancer and have a higher risk for death compared with those with tumors in which ERb is present (Rudolph et al 2012).…”

Clock Genes Show Circadian Rhythms in Salivary Glands

“…Very recently, clock genes have begun to be discovered as key regulators of several diverse diseases, including cancer and diabetes (Krugluger et al, 2007;Mostafaie et al, 2009;Marcheva et al, 2010;Xia et al, 2010;Shimba clock Genes show circadian rhythms in salivary Glands et al, 2011). Saliva plays numerous protective roles for oral tissues maintenance (Mandel, 1989;Dowd, 1999).…”

Circadian Proteins and Genotoxic Stress Response

“…Thus, several reports have demonstrated the reduced expression of Period genes in sporadic and familial breast tumors 65 and hepatocellular carcinoma, 66 and downregulation of Per1 (but not Per2) in colorectal tumors. 67 Some of these changes in expression occur through epigenetic mechanisms. Methylation of the promoter regions of hPer1, hPer2, and hPer3 have been observed in breast cancer, 68 whereas hPer1, hPer2 and hCry1 promoters were hypermethylated in endometrial cancers.…”