Abstract
Carcinogenesis is related to the loss of homeostatic control of cellular processes regulated by transcriptional circuits and epigenetic mechanisms. Among these, the activities of peroxisome proliferator-activated receptors (PPARs) and DNA methyltransferases (DNMTs) are crucial and intertwined. PPARγ is a key regulator of cell fate, linking nutrient sensing to transcription processes, and its expression oscillates with circadian rhythmicity. Aim of our study was to assess the periodicity of PPARγ and DNMTs in pancreatic cancer (PC). We investigated the time-related patterns of PPARG, DNMT1, and DNMT3B expression monitoring their mRNA levels by qRT-PCR at different time points over a 28-hour span in BxPC-3, CFPAC-1, PANC-1, and MIAPaCa-2 PC cells after synchronization with serum shock. PPARG and DNMT1 expression in PANC-1 cells and PPARG expression in MIAPaCa-2 cells were characterized by a 24 h period oscillation, and a borderline significant rhythm was observed for the PPARG, DNMT1, and DNMT3B expression profiles in the other cell lines. The time-qualified profiles of gene expression showed different shapes and phase relationships in the PC cell lines examined. In conclusion, PPARG and DNMTs expression is characterized by different time-qualified patterns in cell lines derived from human PC, and this heterogeneity could influence cell phenotype and human disease behaviour.
Highlights
Cancer statistics rank pancreatic cancer as the fourth leading cause of malignancy-related death worldwide [1], and incidence and mortality rates are very similar, due to difficult early diagnosis, elevated aggressiveness, and chemotherapy resistance
Among the transcriptional regulators an important role is played by the peroxisome proliferatoractivated receptors (PPARs), ligand-activated transcription factors belonging to the superfamily of nuclear hormone receptors, which are considered to be involved in the regulation of nutrient metabolism and energy homeostasis, and in various pathophysiological processes, such as metabolic derangement, inflammation, and cancerogenesis [2]
Circadian rhythmicity is driven at the body level by a central pacemaker and master oscillator located in the hypothalamic suprachiasmatic nuclei (SCN) entrained by the light/dark cycle via the retinohypothalamic tract [21]
Summary
Cancer statistics rank pancreatic cancer as the fourth leading cause of malignancy-related death worldwide [1], and incidence and mortality rates are very similar, due to difficult early diagnosis, elevated aggressiveness, and chemotherapy resistance. Transcriptional mechanisms regulate cell processes underlying cell renewal and comprising proliferation, differentiation, cell death, and PPAR Research apoptosis. PPARs are crucial for the transduction of metabolic and nutritional signals into transcriptional responses and comprise three isoforms, PPARα, PPARβ/δ, and PPARγ, with a high degree of homology but with distinct biological activities [3]. PPARγ expression oscillates over a 24-hour span, and its circadian rhythmicity is crucial in the crosstalk between feeding/fasting cycles, nutrient sensing, metabolic pathways and transcriptional processes. The derangement of this crosstalk is involved in cancer development [8, 9]. Highaffinity synthetic ligands, the thiazolidinedione, prompted the study of PPARγ signalling pathways in the regulation of metabolic processes and are currently evaluated as possible therapeutic tools to take advantage of PPARγ prodifferentiative effects in cancer treatment [10]
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