NFE2L3 as a Novel Biomarker Associated With IL-2/STAT5/NLRP3 Signaling Pathway in Malignant Pleural Mesothelioma and Other Cancers

Our plain-English summary of NFE2L3 as a Novel Biomarker Associated With IL-2/STAT5/NLRP3 Signaling Pathway in Malignant Pleural Mesothelioma and Other Cancers, by Z. Wang, H. Yang, B. Luo, et al (Frontiers in Genetics, 2022).

The study

• Authors: Z. Wang, H. Yang, B. Luo, P. Duan, P. Lin
• Journal: Frontiers in Genetics
• Published: 2022;13:805256
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a malignant tumor originating from pleural mesothelial cells and has a high mortality rate worldwide. With the advent of immunotherapy in MPM treatment, there is an urgent need to elucidate the immune-related mechanisms in this caner. Methods: Single-sample gene set enrichment analysis (ssGSEA) was used to score the immunocytes infiltration of data from different database sources. Identification of immunocyte-related genes was performed with weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs) analysis, and correlation analysis. Pan-caner analysis was performed using "DiffExp" and "Correlation" modules in TIMER. Results: T-helper 2 (Th2) cell was found to be a poor prognostic factor for patients with MPM. Then a transcription factor, NFE2L3, was identified as a biomarker that showed a strong positive correlation with Th2 cell infiltration, and was highly expressed in MPM tissues and was related to the poor prognosis of these patients. At the same time, multiple NFE2L3 methylation sites were negatively correlated with Th2 cell infiltration, and patients with a high degree of methylation enjoy a better prognosis. Pan-caner analysis indicated that NFE2L3 might promote the differentiation of Th2 cells through the IL-2/STAT5/NLRP3 signaling pathway in MPM and many other cancers. Conclusion: We believe that NFE2L3 can serve as a potential biomarker related to the diagnosis and prognosis of patients with MPM, and speculate that NFE2L3 could promote Th2 cell differentiation via IL-2/STAT5/NLRP3 signaling pathway in MPM and many other cancers.

Copyright © 2022 Wang, Yang, Luo, Duan and Lin.

In plain English

This computer-based analysis used malignant pleural mesothelioma (MPM) gene data from public databases, plus tissue staining from surgical patients at Sun Yat-sen University Cancer Center. The data included 85 Cancer Genome Atlas samples, a dataset of 55 MPM and 41 paired normal lung tissues, and a second of 131 tumor samples. The study did not examine asbestos or any other exposure. Patients whose tumors had higher Th2 immune cell levels had a poorer prognosis (p = 0.00014). These levels were estimated from gene-expression data rather than counted directly. Expression of the gene NFE2L3 correlated with these estimated Th2 cell levels (0.47 in the first data source, 0.30 in the second). NFE2L3 expression was higher in MPM than in normal lung parenchyma tissue, and higher expression went with a worse prognosis. Staining found NFE2L3 in tumor cell nuclei but not in normal pleural tissue. In mesothelioma, NFE2L3 correlated with IL-2 receptor genes, STAT5B and NLRP3, but not significantly with STAT5A. The authors hypothesized that NFE2L3 may promote Th2 cell development through this pathway. They noted that the work had no biological validation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Bioinformatics analysis of publicly available gene expression and DNA methylation data, with immunohistochemistry staining of tissue sections
• Who was studied: Malignant pleural mesothelioma samples: 85 TCGA samples; GEO dataset GSE51024 (55 MPM tissues and 41 paired normal lung parenchyma tissues); GEO dataset GSE163720 (131 MPM tumor samples); MPM and normal pleural tissue from surgical patients at Sun Yat-sen University Cancer Center, Guangzhou, China (number not stated)
• Exposure: Not studied: the article did not examine asbestos or any other exposure. It studied gene expression (NFE2L3) and estimated immune cell levels in tumor samples.
• Main results:
  • Immune cell infiltration, including Th2 cells, was estimated (scored) from the expression of 782 immune-related genes, not counted directly
  • MPM patients (TCGA) with high estimated Th2 cell infiltration had a significantly poorer prognosis, p = 0.00014
  • In TCGA samples, NFE2L3 expression had the highest correlation with estimated Th2 cell infiltration (Cor = 0.47)
  • In the validation dataset GSE163720, the correlation between NFE2L3 and Th2 cells was Cor = 0.30
  • NFE2L3 was more highly expressed in MPM tissues than in normal lung parenchyma tissues in GSE51024, p = 5.04e-11
  • Immunohistochemistry showed NFE2L3 mainly in tumor cell nuclei and not in normal pleural tissues
  • In TCGA data, MPM patients with higher NFE2L3 expression had a worse prognosis, p less than 0.0001
  • 9 of 19 NFE2L3 methylation sites were correlated with Th2 cell infiltration, all negatively. Higher methylation at four sites went with better prognosis in MPM patients.
  • In mesothelioma (TIMER, adjusted for tumor purity), NFE2L3 correlated with IL-2RA (Cor = 0.295), IL-2RB (Cor = 0.303) and IL-2RG (Cor = 0.228)
  • In mesothelioma, NFE2L3 correlated with STAT5B (Cor = 0.35). The correlation with STAT5A was not statistically significant.
  • In mesothelioma, NFE2L3 correlated with NLRP3 (Cor = 0.254)
• The authors' conclusion: The authors hypothesized that NFE2L3, which they describe as a novel biomarker in malignant pleural mesothelioma, may promote the differentiation of Th2 cells through the IL-2/STAT5/NLRP3 signaling pathway in multiple cancers.
• Limitations the authors state:
  • The analysis was based only on transcriptome and DNA methylation data from TCGA and GEO, without biological validation. The authors said biological experiments are needed to verify the conclusions.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, Mesothelial Cells, Immunotherapy, Prognosis.

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