Expression of circadian clock gene human Period2 (hPer2) in human colorectal carcinoma

Abstract

BackgroundRecent studies have shown that disruption of circadian rhythms is one of the tumor promoting factors which contribute to mammalian cancer development and progression, but very little is known about the molecular changes of circadian genes in colorectal carcinoma (CRC). Thus, in this study, changes in the expression of human Period2 (hPer2), one of the key circadian clock regulators, in CRC and its correlation with prognosis were investigated.MethodsImmunohistochemical (IHC) staining and real-time PCR for hPer2 were performed for 38 CRC cases.ResultsIHC analysis detected positive staining for hPer2 in 81.6% (31/38) of CRC tissues and 97.4% (37/38) of surrounding non-cancerous tissues (P < 0.05). Most colorectal cells in non-cancerous tissues were homogeneously stained. In contrast, in the paired cancerous tissues, a heterogeneous pattern was found with a significant portion of cancer cells displaying negative or weak hPer2 staining. In over 60% cases (24/38), the staining for hPer2 was much stronger in non-cancerous cells than in the paired cancerous cells. Well-differentiated cancer cells are more likely to maintain hPer2 expression than poorly-differentiated ones. Furthermore, associations of decreased hPer2 levels with patients' age, histological grade, TNM stage and expression of nucleus proliferation related antigen: Ki67 were also detected (P < 0.05). Expression of hPer2 did not correlate with that of either p53 or C-erB-2. Similar to hPer2 protein expression, quantitative RT-PCR for hPer2 also showed decreased mRNA expression in CRC.ConclusionThese results suggest a role for hPer2 in normal colorectal cell function and the potential deregulation of hPer2 expression in the development, invasion, and metastasis of CRC.

Expression of core clock genes in colorectal tumour cells compared with normal mucosa: a systematic review of clinical trials

“…These experimental studies suggested that Period genes control the cell cycle and act as tumour suppressors. This is consistent with the findings in this review where Period is decreased in colorectal tumours . Decreased expression of Period genes has also been reported in other types of cancer such as breast cancer , endometrial carcinoma , non‐small‐cell lung cancer , acute myeloid leukaemia , gliomas and hepatocellular carcinoma .…”

“…1). Characteristics of the 11 studies are given in Table 1 [27][28][29][30][31][32][33][34][35][36][37].…”

The circadian clock and hypoxia in tumor cell de-differentiation and metastasis

“…Bmal1, Npas2 and Clock have been indicated as important for VEGF-production during the night [33,34]. In agreement with these findings, Clock is often up-regulated and Period2 downregulated in human colorectal cancer and the levels of tumor Clock expression exhibit a tight positive correlation with tumor VEGF-levels and metastatic dissemination in patients [35,36].…”

Circadian angiogenesis

“…From a molecular point of view, and in agreement with the findings from pre-clinical models, CLOCK was reported to be significantly up-regulated and Per2 was down-regulated in human colorectal cancer tumors compared to adjacent healthy tissue and the levels of CLOCK from different patients strongly correlated with the level of VEGF detected in their tumor biopsies as well as degree of metastatic dissemination of tumor cells and poor prognosis (91,92). In addition, other angiogenic factors have been found to oscillate in a circadian fashion, including bFGF, EGF and IGFBP in breast cancer patients, where peak plasma levels are generally found during the day and low levels in the night (93).…”