Abstract
BackgroundAdenocarcinoma of the pancreas is one of the most aggressive tumor diseases affecting the human body. The oncogenic potential of pancreatic cancer is mainly characterized by extremely rapid growth triggered by the activation of oncogenic signaling cascades, which suggests a change in the regulation of important transcription factors. Amongst others, NFAT transcription factors are assumed to play a central role in the carcinogenesis of pancreatic cancer. Recent research has shown the importance of the transcription factor Sp1 in the transcriptional activity of NFATc2 in pancreatic cancer. However, the role of the interaction between these two binding partners remains unclear. The current study investigated the role of Sp1 proteins in the expression of NFATc2 target genes and identified new target genes and their function in cells. A further objective was the domain of the Sp1 protein that mediates interaction with NFATc2.The involvement of Sp1 proteins in NFATc2 target genes was shown by means of a gene expression profile analysis, and the results were confirmed by quantitative RT-PCR. The functional impact of this interaction was shown in a thymidine incorporation assay. A second objective was the physical interaction between NFATc2 and different Sp1 deletion mutants that was investigated by means of immunoprecipitation.ResultsIn pancreatic cancer, the proto-oncogene c-Fos, the tumor necrosis factor TNF-alpha, and the adhesion molecule integrin beta-3 are target genes of the interaction between Sp1 and NFATc2. Loss of just one transcription factor inhibits oncogenic complex formation and expression of cell cycle-regulating genes, thus verifiably decreasing the carcinogenic effect. The current study also showed the interaction between the transcription factor NFATc2 and the N-terminal domain of Sp1 in pancreatic cancer cells. Sp1 increases the activity of NFATc2 in the NFAT-responsive promoter.ConclusionsThe regulation of gene promotors during transcription is a rather complex process because of the involvement of many proteins that – as transcription factors or co-factors – regulate promotor activity as required and control cell function. NFATc2 and Sp1 seem to play a key role in the progression of pancreatic cancer.
Highlights
Adenocarcinoma of the pancreas is one of the most aggressive tumor diseases affecting the human body
The lysates were assessed in the expression profile analysis that contained 89 different genes involved in the carcinogenesis of pancreatic cancer
The results showed reduced synthesization of the molecules Apoptotic protease activating factor 1 (APAF1), Ataxia telangiectasia (ATM), B-cell lymphoma 2 (BCL2), Breast cancer 1 (BRCA1), and TNFRSF25 involved in apoptosis, of the adhesion molecules integrin alpha-2 and integrin beta-3, of the metastasis suppressor gene Metastasis suppressor gene 1 (MTSS1), as well as of phosphoinositide-3-kinase PI3K (Fig. 1c-k)
Summary
Adenocarcinoma of the pancreas is one of the most aggressive tumor diseases affecting the human body. The involvement of Sp1 proteins in NFATc2 target genes was shown by means of a gene expression profile analysis, and the results were confirmed by quantitative RT-PCR. On the basis of this knowledge, a tumor progression model was developed (2019) 20:2 describing the gradual process of pancreatic cancer from its neoplastic preliminary stage – termed PanIN (pancreatic intraepithal neoplasia) – to its malignant stage [7]. This process involves various mutations and genetic changes such as oncogene mutations, changes in tumor suppressor genes, as well as over-expression of growth factors and their receptors [8]. This series of mutations upsets the balance between tumor-suppressing and tumor-promoting pathways
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