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.
Highlights
Recent 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)
Immunohistochemical analyses of human Period2 (hPer2) protein expression To investigate whether hPer2 gene was deregulated in colorectal cancer, we first examined hPer2 protein expression in 38 paired colorectal cancerous and noncancerous tissues by IHC staining. hPer2 expression was found in both cytoplasm, and nucleus
Welldifferentiated cancer cells tend to have comparable hPer2 level with that in non-cancerous cells (Figure 2), suggesting that loss of hPer2 expression may associate with increased aggressiveness
Summary
Recent 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). In this study, changes in the expression of human Period (hPer2), one of the key circadian clock regulators, in CRC and its correlation with prognosis were investigated. In terms of the mechanisms, C-erB-2 and p53 were suggested to act as the downstream players for hPer in the course of tumor progression [7,10,14] Both the C-erbB-2 oncogene and the p53 tumor-suppressor gene integrate numerous signals that control cell proliferation and survival. Whether hPer expression is associated with other tumor-associate proteins such as C-erB-2 and p53 in human CRC remains uncertain
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