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Primers on molecular pathways--the NFAT transcription pathway in pancreatic cancer.

ABSTRACT: The calcineurin-responsive nuclear factor of activated T cells (NFAT) family of transcription factors was originally identified as a group of inducible nuclear proteins, which regulate transcription during T lymphocyte activation. However, following their initial discovery, a multitude of studies quickly established that NFAT proteins are also expressed in cells outside the immune system, where they participate in the regulation of the expression of genes influencing cell growth and differentiation. Ectopic activation of individual NFAT members is now recognized as an important aspect for oncogenic transformation in several human malignancies, most notably in pancreatic cancer. Sustained activation of the Ca(2+)/calcineurin/NFAT signaling pathway has emerged as a powerful regulatory principle governing pancreatic cancer cell growth. Activated NFAT proteins form complexes with key oncogenic proteins to regulate the transcription of master cell cycle regulators and proteins with functions in cell survival, migration and angiogenesis. This review pays particular attention to recent advances in our understanding of how the NFAT transcription pathway controls gene expression during development and progression of pancreatic cancer. and IAP.

SUBMITTER: Konig A

PROVIDER: S-EPMC3114309 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Primers on molecular pathways--the NFAT transcription pathway in pancreatic cancer.

König Alexander A Fernandez-Zapico Martin E ME Ellenrieder Volker V

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 20100819 4

The calcineurin-responsive nuclear factor of activated T cells (NFAT) family of transcription factors was originally identified as a group of inducible nuclear proteins, which regulate transcription during T lymphocyte activation. However, following their initial discovery, a multitude of studies quickly established that NFAT proteins are also expressed in cells outside the immune system, where they participate in the regulation of the expression of genes influencing cell growth and differentiat ...[more]

PMID: 20720442

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Project description:Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies, with an overall life expectancy of 6 months. Despite considerable advances in the understanding of the molecular mechanisms involved in the carcinogenesis of PDAC, the outcome of the disease was not significantly improved over the last 20 years. Although some achievements in molecular-targeted therapies have been made (that is, targeting the epidermal growth factor receptor by erlotinib), which already entered clinical settings, and despite the promising outcome of the FOLFIRINOX trial, there is an urgent need for improvement of the chemotherapy in this disease. A plethora of molecular alterations are thought to be responsible for the profound chemoresistance, including mutations in oncogenes and tumor suppressors. Besides these classical hallmarks of cancer, the constitutive or inducible activity of transcription factor pathways are characteristic changes in PDAC. Recently, three transcription factors-nuclear factor-κB (NF-κB), nuclear factor of activated T cells (NFAT) and nuclear factor-E2-related factor-2 (Nrf2)-have been shown to be crucial for tumor development and chemoresistance in pancreatic cancer. These transcription factors are key regulators of a variety of genes involved in nearly all aspects of tumorigenesis and resistance against chemotherapeutics and death receptor ligands. Furthermore, the pathways of NF-κB, NFAT and Nrf2 are functional, interacting on several regulatory steps, and, especially, natural compounds such as curcumin interfere with more than one pathway. Thus, targeting these pathways by established inhibitors or new drugs might have great potential to improve the outcome of PDAC patients, most likely in combination with established anticancer drugs. In this article, we summarize recent progress in the characterization of these transcription-factor pathways and their role in PDAC and therapy resistance. We also discuss future concepts for the treatment of PDAC relying on these pathways.

Project description:BackgroundTumor necrosis factor (TNF) family members play a vital role in anticancer therapy. This study aimed to screen the critical markers for the prognostic analysis of pancreatic adenocarcinoma (PAAD) by analyzing the clustering patterns of TNF family members in PAAD.MethodsIn this study, the NMF clustering method was adopted to cluster samples from The Cancer Genome Atlas (TCGA) to acquire the clustering pattern of the TNF family in PAAD. Differential gene analysis was performed according to TNF family gene clusters. The support vector machine (SVM) method was conducted for further gene screening, and the risk score model of the screened genes was constructed by Lasso. The single sample gene set enrichment analysis (ssGSEA) method was adopted for immunoenrichment analysis and tumor immune cycle analysis. Genes associated with risk scores were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis.ResultsWe clustered PAAD into two groups based on TNF family genes. Nineteen TNF family genes were significantly associated with the clinical characteristics of PAAD patients. The risk score formula was composed of RHOD, UBE2C, KLHDC7b, MSLN, ADAM8, NME3, GNG2, and MCOLN3. GSE57495 and GSE62452 datasets verified that patients in the high-risk group had a worse prognosis than those in the low-risk group. The risk score-related genes analyzed by GO and KEGG were mainly involved in the modulation of chemical synaptic transmission and synaptic vesicle cycle pathway. There were significant differences in the expression of 15 immune cells between the high-risk group and the low-risk group. The risk score was positively correlated with HCK, interferon, MHC-I, and STAT1. The expression of genes relevant to chemokine, immunostimulator, MHC, and receptor was strongly associated with the risk score.ConclusionThe risk score model based on the TNF family can predict the prognosis and immune status of PAAD patients. Further research is needed to verify the clinical prognostic value of risk scores.

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Primers on molecular pathways--the NFAT transcription pathway in pancreatic cancer.

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Primers on molecular pathways--the NFAT transcription pathway in pancreatic cancer.

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