Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality rates. PDAC initiation and progression are promoted by genetic and epigenetic dysregulation. Here, we aimed to characterize the PDAC DNA methylome in search of novel altered pathways associated with tumor development. We examined the genome-wide DNA methylation profile of PDAC in an exploratory cohort including the comparative analyses of tumoral and non-tumoral pancreatic tissues (PT). Pathway enrichment analysis was used to choose differentially methylated (DM) CpGs with potential biological relevance. Additional samples were used in a validation cohort. DNA methylation impact on gene expression and its association with overall survival (OS) was investigated from PDAC TCGA (The Cancer Genome Atlas) data. Pathway analysis revealed DM genes in the calcium signaling pathway that is linked to the key pathways in pancreatic carcinogenesis. DNA methylation was frequently correlated with expression, and a subgroup of calcium signaling genes was associated with OS, reinforcing its probable phenotypic effect. Cluster analysis of PT samples revealed that some of the methylation alterations observed in the Calcium signaling pathway seemed to occur early in the carcinogenesis process, a finding that may open new insights about PDAC tumor biology.

Pan-Cancer Analysis of NOS3 Identifies Its Expression and Clinical Relevance in Gastric Cancer

“…And researches also reported that ATP-binding cassette transporter G1 (ABCG1), a member of ABC transporter family, could modulate the interaction of Cav-1 and NOS3 protein in endothelial cells (ECs), and increase cell migration through Lyn/Akt/ NOS3 in endothelial progenitor cells (EPCs). “KEGG_CALCIUM_SIGNALING_PATHWAY” contributes to many crucial tumor pathology processes, including proliferation, invasion, cell death, and autophagy in many tumors ( 42 – 45 ). As described above, the increased concentration of Ca 2+ could induce the combination of CaM protein and NOS3 protein, and subsequently stimulate the activity of NOS3 protein ( 2 , 46 ).…”

Altered DNA methylation in ion transport and immune signalling genes is associated with severity in Pancreatic Ductal Adenocarcinoma

“…Late diagnosis, treatment failure, and loco-regional recurrences contribute to its poor prognosis (Ansari et al, 2016). Along with genetic alterations, studies in the past decade showed that epigenetic alterations contribute to PDAC development and pathogenesis (Mazor et al, 2016, Mishra and Guda, 2017; Gregório et al, 2020). Studies also showed that precancerous lesions of PDAC harbour DNA methylation alterations in the known epigenetic driver genes (Bararia et al, 2020).…”

“…The calcium and potassium ion channels thus can inhibit T-cell activation and proliferation upon antigen recognition, creating an immunosuppressive or immune evasive tumor microenvironment in PDAC, which is again associated with poor prognosis and recurrence. Hypermethylation of potassium channels may thus alter the immune context in PDAC and limit antitumor immunity (Patel et al, 2019).A recent study documented epigenetic dysregulation (hypermethylation) of Calcium ion transporters in PDAC (Gregório et al, 2020). This study had further shown that epigenetic modification in Calcium signalling occurred at early stages of PDAC.…”

Store-Operated Calcium Entry: Shaping the Transcriptional and Epigenetic Landscape in Pancreatic Cancer

“…This deregulation elicits a crucial shift in pancreatic cancer, as calcium is a major second messenger of several intracellular signaling cascades, influencing various cellular processes, such as transcription, metabolism, stress response [ 8 , 9 , 35 ]. Consistently, the de-regulation of calcium signaling and homeostasis is tightly associated with pancreatitis, which is a major risk factor for pancreatic cancer [ 36 , 37 , 38 , 39 , 40 ], and has been suggested to take place early in PDAC development [ 41 ]. In fact, several genes associated with calcium signaling have been shown to be differentially methylated upon pancreatic cancer development [ 41 ].…”

“…Consistently, the de-regulation of calcium signaling and homeostasis is tightly associated with pancreatitis, which is a major risk factor for pancreatic cancer [ 36 , 37 , 38 , 39 , 40 ], and has been suggested to take place early in PDAC development [ 41 ]. In fact, several genes associated with calcium signaling have been shown to be differentially methylated upon pancreatic cancer development [ 41 ]. Thus, there is a need to better elucidate the role of calcium signaling deregulation in pancreatic cancer.…”