Aberrant Expression of Clock Gene Period1 and Its Correlations with the Growth, Proliferation and Metastasis of Buccal Squamous Cell Carcinoma

Abstract

Period1 (PER1) is an important core clock gene, which regulates normal cell proliferations and physiological rhythms of human beings. Recent studies have showed aberrant expressions and altered rhythms of PER1 were highly correlated to the carcinogenesis and development of malignant tumors. However, there is no study on the correlation of aberrant expressions and altered rhythms of PER1 with the growth, proliferation and metastasis of buccal squamous cell carcinoma (BSCC). In this study, PER1 and MMP-2 expression in the cancerous and adjacent noncancerous tissues of 38 patients with BSCC and its correlations with patients' clinical pathologic characteristics were investigated. A mouse model of BSCC was also established and mice were sacrificed at 4 different time points in a period of 24 hours. Xenografted tumor weight, proliferation index (PI), and mitotic index (MI) of tumors in the 4 time groups were detected. Results showed that PER1 expression was significantly down-regulated in cancerous tissues of patients with BSCC (P<0.05). PER1 expression was significantly down-regulated in patients of T3∼T4 staging and those with lymph node metastasis compared to that of T1∼T2 staging and those without lymph node metastasis (P<0.05), respectively. PER1 mRNA expression, MI and tumor weight had significant differences among the 4 time groups, which PI all confirmed to circadian rhythms. MI, PI, MMP-2 mRNA and tumor weight had negative correlation with PER1 mRNA expression. Peak value of PER1 mRNA expression and trough values of MI, PI and tumor weight all appeared in middle activity phase, whereas trough value of PER1 mRNA expression and peak values of MI, PI and tumor weight all occurred in middle rest phase. Our study suggested that aberrant expression of PER1 had significant correlation with the growth, proliferation and metastasis of BSCC and it might act as an anti-oncogene.

Circadian clock-mediated control of stem cell division and differentiation: beyond night and day

“…For example, elimination of the SCN 'master clock' results in tumor growth two to three times faster than in controls (Filipski et al, 2002). Consistent with the possible importance of this regulation, clock protein misexpression and/or a lack of circadian control has been documented in multiple tumor types (Hwang-Verslues et al, 2013; Luo et al, 2012;Zhao et al, 2013) and immortalized cell lines (Yeom et al, 2010). In normal physiology, circadian cell division has been documented in adult hippocampal neurogenesis (BouchardCannon et al, 2013), in intestinal and skin epithelial cell division (Geyfman et al, 2012;Janich et al, 2013;Karpowicz et al, 2013), and in multiple immune cell populations (Fortier et al, 2011;Keller et al, 2009) -essentially anywhere that cell division occurs in adult animals.…”

The circadian clock gene PER2 plays an important role in tumor suppression through regulating tumor-associated genes in human oral squamous cell carcinoma

“…In addition to the cell cycle genes, we speculate that there may be CCGs regulated by PER2. Second, carcinogenesis is a complex process involving cell proliferation, apoptosis, invasion, metastasis and tumor angiogenesis (4,6,8,9,31). It remains unclear, then, whether these tumor-related genes were modulated specifically by PER2.…”

“…Clock genes are the core that constitutes the circadian clock, within virtually every cell in the body (6,7). To date, at least 14 core clock and clock-related genes have been reported, including PER1, PER2, PER3, Cry1, Cry2, Clock Bmal1, TIM, CK1ε, NPAS2, REV-ERBs, Dec1, Dec2, and RORs (3,(8)(9)(10). Clock genes have three important functions.…”

The contribution of circadian rhythms to cancer formation and mortality

“…Tissue samples from 32 patient skin biopsies revealed lower mRNA levels of the same circadian genes excluding Cry2 that were seen in of both malignant melanoma and nonmalignant nevus tumors compared to surrounding skin tissue (Lengyel et al, 2013). Downregulation of PER1 was also shown in tissue collected from 38 patients who had been diagnosed but not yet treated for buccal squamous cell carcinoma; this effect was significantly correlated with increased risk of metastasis and clinical stage, where more severe risk and diagnosis corresponded with more PER1 downregulation (Zhao et al, 2013). Nevertheless, the studies described above have their limitations since they all collected their human tissue samples from a single three hour period and did not categorize tissue by collection time (Zhao et al, 2013).…”

“…Downregulation of PER1 was also shown in tissue collected from 38 patients who had been diagnosed but not yet treated for buccal squamous cell carcinoma; this effect was significantly correlated with increased risk of metastasis and clinical stage, where more severe risk and diagnosis corresponded with more PER1 downregulation (Zhao et al, 2013). Nevertheless, the studies described above have their limitations since they all collected their human tissue samples from a single three hour period and did not categorize tissue by collection time (Zhao et al, 2013). While these studies do not measure the target genes over time due to practical considerations of subject burden, since they all compare the cancerous tissue to non-cancerous tissue collected at the same time from the same patient, the compared samples do provide important information related to protein abundance of circadian components and cancer risk.…”