Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer

Abstract

Recent studies have demonstrated that abnormal expression of the clock gene PER2 is closely associated with the development of a variety of cancer types. However, the expression of PER2 in oral squamous cell carcinoma (OSCC), a common malignant tumor in humans, and its correlations with the clinicopathological parameters and survival time of OSCC patients and the altered expression of important tumor-related genes remain unclear. In the present study, we detected the mRNA and protein expression levels of PER2, PIK3CA, PTEN, P53, P14ARF and caspase‑8 in OSCC tissues and cancer-adjacent oral mucosa by reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemistry. The results showed that the PER2, PTEN, P53, P14ARF and caspase‑8 mRNA and protein expression levels in OSCC were significantly reduced compared with those in cancer-adjacent tissues. Additionally, the PIK3CA protein expression level was significantly increased in OSCC tissues, whereas the mRNA level was not. Decreased expression of PER2 was significantly associated with advanced clinical stage and the presence of lymphatic metastasis in OSCC patients. Patients with PER2‑negative expression had a significantly shorter survival time than those with PER2‑positive expression. PER2 expression was negatively correlated with PIK3CA and P53 levels, and positively correlated with PTEN, P14ARF and caspase‑8 levels. In summary, the results of this study suggest that loss of PER2 expression is closely associated with the genesis and development of OSCC and that PER2 may be an important prognostic biomarker in OSCC. PER2 may serve an antitumor role via the P53/P14ARF, PIK3CA/AKT and caspase‑8 pathways.

Overexpression of the clock gene Per2 suppresses oral squamous cell carcinoma progression by activating autophagy via the PI3K/AKT/mTOR pathway

“…It is characterized by noteworthy tumor suppressor effects [11,12,25,26]. We also found previously that Per2 is expressed at lower levels in OSCC tissues and is markedly associated with the clinical stage and survival time of patients [21]. The above studies suggest that Per2 is an important tumor suppressor gene, but its antineoplastic mechanism is ambiguous, so it is of great significance to further examine its underlying mechanism.…”

“…Per2 is an important core clock gene [6,15], and existing studies have reported that Per2 expression is strikingly lower in a number of human cancers, such as gastric cancer and non-small cell lung cancer, and closely related to the development and progression of cancer [17][18][19][20]. Xiong H et al found that Per2 is expressed at lower levels in OSCC tissues and is significantly associated with the clinical stage and survival time of patients [21]. These reports suggest that Per2 is a crucial tumor suppressor gene, but its specific mechanism of tumor suppression is unknown.…”

Circadian Rhythm Is Disrupted by ZNF704 in Breast Carcinogenesis

“…Dysfunction of circadian clock has been linked to the development and progression of tumors (Altman et al, 2014;Yeh et al, 2014;Yu & Weaver, 2011), yet the regulation and deregulation of core clock genes in tumorigenesis is less understood. Among the clock genes, PER2 dysregulation or deletion is also frequently observed in malignancies from a broad spectrum of tissue origins, and these aberrations are associated with a more aggressive phenotype and accordingly poorer survival of the cancer patients (Liu et al, 2014;Xiong et al, 2018;Zhao et al, 2014). Of note, PER2 promoter hypermethylation is detected in endometrial cancer (Shih et al, 2010) and glioma (Fan et al, 2014), suggesting that transcriptional regulation of PER2 is pathologically relevant to tumor development and progression.…”

Clock genes alterations and endocrine disorders

“…127 In vivo and in vitro studies have demonstrated that disruption of circadian rhythms is linked to tumour progression and mammalian tumorigenesis for several malignancies such as liver cancer, 128 oral squamous cell carcinoma, 129 gastric, pancreatic and colorectal carcinoma. 127 In vivo and in vitro studies have demonstrated that disruption of circadian rhythms is linked to tumour progression and mammalian tumorigenesis for several malignancies such as liver cancer, 128 oral squamous cell carcinoma, 129 gastric, pancreatic and colorectal carcinoma.…”

“…Lately, circadian disruption has been recognized as a potential independent risk factor for cancer development. 127 In vivo and in vitro studies have demonstrated that disruption of circadian rhythms is linked to tumour progression and mammalian tumorigenesis for several malignancies such as liver cancer, 128 oral squamous cell carcinoma, 129 gastric, pancreatic and colorectal carcinoma. 130 Clock genes contribute to the occurrence and development of tumours by regulating and interfering with oncogenes (c-myc), tumoursuppressor genes (P53 and P21), genes involved in the regulation of the cell cycle and vascular endothelial growth factor.…”