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.
Highlights
Since nuclear factor of activated T cells (NFAT) was identified as an activator for the transcription of interleukin-2 in T-cells, there has been increasing evidence linking NFAT proteins to the transcription of a variety of genes [1]
Since the first study regarding the correlation between NFAT1/5 and cancer cells was published [6], one or more members of the NFAT family have been reported to be dysregulated in numerous cancer types including hepatocellular carcinoma (HCC) [7, 8], breast cancer [9, 10], colorectal cancer [11, 12], and lung cancer (LC) [13,14,15]
NFAT2 mRNA expression was significantly lower in patients with LC in four datasets than that in corresponding normal tissues
Summary
Since nuclear factor of activated T cells (NFAT) was identified as an activator for the transcription of interleukin-2 in T-cells, there has been increasing evidence linking NFAT proteins to the transcription of a variety of genes [1]. The calcium-regulated NFAT 1/2/3/ 4 were activated by increased intracellular calcium levels via dephosphorylation by calcineurin, whereas NFAT5 lacks the calcineurin docking site and is activated by osmotic stress [3]. NFAT proteins were originally found to regulate genes related to the development, activation, and differentiation of immune cells [4], thereby playing critical roles in immune systems. Subsequent studies have indicated that NFAT family members are expressed in non-immune cells and tissues, participating in many normal bodily processes as well as in the development of several diseases including cancer [5]. Since the first study regarding the correlation between NFAT1/5 and cancer cells was published [6], one or more members of the NFAT family have been reported to be dysregulated in numerous cancer types including hepatocellular carcinoma (HCC) [7, 8], breast cancer [9, 10], colorectal cancer [11, 12], and lung cancer (LC) [13,14,15]
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