Expression, Prognosis and Gene Regulation Network of NFAT Transcription Factors in Non-Small Cell Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. The nuclear factor of activated T cells (NFAT) family is implicated in tumorigenesis and progression in various types of cancer. However, little is known about their expression patterns, distinct prognostic values, and potential regulatory networks in NSCLC. In this study, we comprehensively analyzed the distinct expression and prognostic value of NFATs in NSCLC through various large databases, including the Oncomine, UCSC Xena Browser, UALCAN databases, Kaplan–Meier Plotter, cBioPortal, and Enrichr. In lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), NFAT1/2/4/5 mRNA expression levels were significantly decreased and NFAT3 mRNA expression level was significantly increased. The cBioPortal database analysis showed that the mRNA dysregulation was one of the single most important factors for NFAT alteration in LUAD and LUSC and that both LUAD and LUSC cases with the alterations in the mRNA expression of NFATs had significantly better overall survival (OS). High expression levels of NFAT1/2/4/5 were significantly associated with better OS in LUAD, whereas high NFAT3 expression led to a worse OS. Overexpression of NFAT1/2 predicted better OS in LUSC, whereas high NFAT5 expression led to a worse OS. The networks for NFATs and the 50 most frequently altered neighbor genes in LUAD and LUSC were also constructed. NFATs and genes significantly associated with NFAT mRNA expression in LUAD and LUSC were significantly enriched in the cGMP-dependent protein kinase and Wnt signaling pathways. These results showed that the NFAT family members displayed varying degrees of abnormal expressions, suggesting that NFATs may be therapeutic targets for patients with NSCLC. Aberrant expression of NFATs was found to be associated with OS in the patients with NSCLC; among NFATs, NFAT3/4 may be new biomarkers for the prognosis of LUAD. However, further studies are required to validate our findings.

How does NFAT3 regulate the occurrence of cardiac hypertrophy?

“…NFAT3 binds to other transcription factors in the nucleus to promote the expression of hypertrophy-related genes. Studies have shown that NFAT3 plays a role in a variety of cells and tissues, such as hippocampal cells [96] , [97] , tumour cells [98] , [99] , [100] , [101] , [102] , [103] , and lungs [104] , [105] . Several molecules have been shown to modulate NFAT3 in noncardiac cells; for example, cAMP inhibits Ca 2+ -induced nuclear export of the MEF2 corepressor HDAC5 and prevents Ca 2+ -stimulated nuclear import of the MEF2 coactivator NFAT3/c4 [106] .…”

NFATc2 promotes lactate and M2 macrophage polarization through USP17 in lung adenocarcinoma

“…The nuclear factor of activated T cell (NFAT) family is multifunctional. NFATs promote cell growth, drug resistance, and tumorigenesis by regulating transcriptional activation of target genes [11,12]. In particular, NFATc2 can enhance tumor-initiating characteristics including self-renewal, cell motility, and tumorigenesis in lung adenocarcinoma, and high expression of this protein was associated with poor outcomes of patients with this disease [13].…”

Evaluation of Expression Levels of NFATc2 and PPARG Genes Two Effector Elements of WNT Pathway in Non-Small Cell Lung Carcinoma

“…Also, they suggested that the NFAT family members divulged different degrees of aberrant expressions, advocating that NFATs might be therapeutic targets for NSCLC patients. [ 8 ] In another study, the researcher found that abnormal expression of the NFATc1 and NFATc3 might be involved in the incidence of NSCLC as well as Brain metastases through modulating IL-11, CDH5, and CCL2. [ 9 ]…”