Expression of cell cycle regulatory factors hus1, gadd45a, rb1, cdkn2a and mre11a correlates with expression of clock gene per2 in human colorectal carcinoma tissue

Abstract

Deregulated expression of clock gene per2 has previously been associated with progression of cancer. The aim of the present study was to identify genes related to per2 expression and involved in cell cycle control. Patients surgically treated for colorectal carcinoma with up-regulated and down-regulated per2 expression in cancer versus adjacent tissue were studied. Total RNA from cancer tissue of these patients was used to specify genes associated with altered per2 expression using the Human Cell Cycle RT(2) profiler PCR array system. We identified seven genes positively correlated (hus1, gadd45α, rb1, cdkn2a, cdk5rp1, mre11a, sumo1) and two genes negatively correlated (cdc20, birc5) with per2 expression. Expression of these seven genes was subsequently measured by real time PCR in all patients of the cohort. Patients were divided into three groups according to TNM classification. We observed an increase in gene expression in cancer tissue compared to adjacent tissue in the first group of patients in all genes measured. Expression of genes positively associated with per2 gene expression was dependent on tumor staging and changes were observed preferentially in cancer tissue. For genes negatively associated with per2 expression we also detected changes in expression dependent on tumor staging. Expression of cdc20 and birc5 was increasing in the proximal tissue and decreasing in the cancer tissue. These results implicate functional involvement of per2 in the process of carcinogenesis via newly uncovered genes. The relevancy of gene expression for determination of diagnosis and prognosis should be considered in relation to tumor staging.

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

“…Recent studies have considered that clock gene PER2 can regulate cell cycle genes, sequentially, producing a close relationship with the occurrence of cancers (14,(27)(28)(29). In the present study, however, we considered questions on two other aspects.…”

“…PER2 is reduced in various types of cancer cells, including breast cancer, neck squamous cell carcinoma, prostate cancer, colorectal cancer, hepatocellular carcinoma, skin cancer, gastric cancer, and myeloid leukemia (1,10,14,(20)(21)(22)(23)(24)(25)(26). PER2 can regulate downstream plentiful cell cycle genes, such as CyclinA, CyclinB1, CyclinD1, CyclinE, p53, and C-myc (14,(27)(28)(29). Our previous study also demonstrated that PER2 expression is decreased in oral squamous cell carcinoma (OSCC) (13), and lower expression of PER2 in OSCC cells increased the expression of downstream cell cycle genes, such as CyclinA2, CyclinB1, CyclinD1, CDK4, CDK6, and E2F1, and decreased expression of p53, p16, and p21 (30).…”

Targeting Cdc20 as a novel cancer therapeutic strategy

“…Moreover, Cdc20-resistant conductin suppressed Wnt signaling and subsequently attenuated colony formation of colorectal cancer cells (Hadjihannas et al, 2012). Interestingly, in a separate study, it has also been observed that expression of Cdc20 was decreased in the human colorectal cancer tissues compared with the proximal tissues (Storcelova et al, 2013), suggesting that further in-depth investigation is needed to define the exact role of Cdc20 in colorectal cancer.…”

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

“…Multiple intracellular signaling proteins involved in stress-responsive cascades, e.g . ATM, p53, MRE11, BRCA1 and CDKN2A, play important roles in both cell cycle/DDR control as well as circadian clock regulation [24, 26, 28-30]. Recently we have also demonstrated that G protein-coupled receptor (GPCR)-related signaling proteins, linked to premature aging, can also effectively connect energy metabolism, oxidative stress responses and DDR activity [31-34].…”