Circadian gene expression and clinicopathologic correlates in pancreatic cancer.
INTRODUCTION: The circadian rhythm is responsible for physiologic homeostasis, behavior, and components of multiple metabolic processes. Disruption of the circadian rhythm is associated with cancer development, and several circadian clock genes have been implicated in loss of cell cycle control, impaired DNA damage repair, and subsequent tumor formation. Here, we investigated the expression profiles of several circadian clock genes in pancreatic ductal adenocarcinoma (PDA). METHODS: Quantitative real-time polymerase chain reaction was used to examine the circadian clock genes (brain-muscle-like (Bmal)-ARNTL, circadian locomotor output cycles kaput (Clock), cryptochrome 1 (Cry1), cryptochrome 2 (Cry2), casein kinase 1ε (CK1ε), period 1 (Per1), period 2 (Per2), period 3 (Per3), timeless (Tim), and timeless-interacting protein (Tipin)) in PDA, as well as matching adjacent and benign tissue. Logistic regression models with robust variance were used to analyze the gene expression levels, and Kaplan-Meier survival curves were generated based on gene expression. RESULTS: In the tumor tissue of PDA patients, compared to their matched adjacent tissue, expression levels of all circadian genes were lower, with statistical significance for Per1, Per2, Per3, Cry1, Cry2, Tipin, Tim, CK1ε, Bmal-ARNTL, and Clock (p < 0.025). PDA tumors also expressed significantly lower levels of the circadian genes when compared to benign lesions for Per1, Per2, Per3, Cry2, Tipin, and CK1ε. A significant association between low levels of expression in the tumors and reduced survival was found with Per1, Per2, Per3, Cry2, Tipin, CK1ε, Clock, and Bmal-ARNTL. CONCLUSIONS: Our results reveal for the first time a dysregulated transcription of several circadian genes in PDA. Elevation of the gene levels in the benign and matched adjacent tissues may be indicative of their role during the process of tumorigenesis. The potential of using circadian genes as predictive markers of the outcomes and survival and distinguishing PDA from benign pancreas must be studied in larger populations to validate and demonstrate their eventual clinical utility.
Relles, D; Sendecki, J; Chipitsyna, G; Hyslop, T; Yeo, CJ; Arafat, HA
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