Carcinogenesis relates to the loss of homeostatic control of cellular processes

Carcinogenesis relates to the loss of homeostatic control of cellular processes regulated by transcriptional circuits and epigenetic mechanisms. were characterized by a 24?h period oscillation and a borderline significant rhythm was observed for the 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 and expression is characterized by different time-qualified patterns Rabbit Polyclonal to SLC16A2. in cell lines derived from human PC and this heterogeneity could influence cell phenotype and human disease behaviour. NPS-2143 1 Introduction 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. Bad prognosis and lack of effective treatment are responsible for high lethality so that there is certainly pressing have to determine molecular biomarkers for prognostic assessment and target therapy. The preservation of tissue integrity is critical for organism survival and relies on tissue renewal driven by stem cells that are capable of responding to injury and repairing tissue damage caused by physical chemicals microbial and mutagenic agents. Transcriptional mechanisms regulate cell processes underlying cell renewal and comprising proliferation differentiation cell death and apoptosis. Carcinogenesis relies on the loss of homeostatic mechanisms regulating cell proliferative differentiative and survival processes. Among the transcriptional regulators an important role is played by the peroxisome proliferator-activated 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]. PPARs are crucial for the transduction of metabolic and nutritional signals into transcriptional responses and comprise three isoforms PPARis mainly involved in NPS-2143 lipid metabolism NPS-2143 the function of PPARis not entirely clear and PPARregulates cell fate and differentiation decisions as well as adipogenesis and fat storage [4-7]. PPARexpression 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 High-affinity synthetic ligands the thiazolidinedione prompted the study of PPARsignalling pathways in the regulation of metabolic processes and are currently evaluated as possible therapeutic tools to take advantage of PPARprodifferentiative effects in cancer treatment [10]. Transcriptional processes are regulated also by epigenetic mechanisms such as acetylation/deacetylation and methylation/demethylation. DNA methyltransferases (DNMTs) play a critical role in epigenetic mechanisms attaching methyl groups to NPS-2143 DNA and in particular DNMT1 keeps up the methylation pattern during DNA replication whereas DNMT3a and DNMT3b primarily catalyze methylation [11-13]. An intriguing interaction between PPARand DNMTs has been recently suggested by the downregulation of DNA methyltransferases evidenced in immune cells following ligand-dependent PPARactivation [14]. The aim of our study was to assess the time-related patterns of variation of PPARand DNMTs in pancreatic cancer using models represented by pancreatic cancer cell lines evaluated after synchronization. 2 Material and Methods 2.1 Cell Culture and Serum Shock Procedures BxPC-3 CFPAC-1 PANC-1 and MIA PaCa-2 cells were cultured at 37°C in 5% CO2 atmosphere in DMEM medium supplemented with 10% fetal bovine serum (FCS) 100 penicillin and 100?ng/mL streptomycin (Invitrogen Life Technologies Milan Italy) while CFPAC-1 and MIA PaCa-2 were maintained in RPMI medium (Invitrogen Life Technologies Milan Italy). Cell synchronization was obtained by means of serum shock.

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