Identification roles of NFE2L3 in digestive system cancers

Abstract

Background: Morbidity and mortality rates of Digestive System Cancers (DSC) continue to pose human lives and health. Nuclear factor erythroid 2-like protein 3 (NFE2L3) is aberrantly expressed in DSC. This study aimed to explore the clinical value and underlying mechanisms of NFE2L3 as a novel biomarker in DSC.

Methods: We utilized data from databases and clinical gastric cancer specimens to validate the aberrant expression level of NFE2L3 and further assessed the clinical value of NFE2L3. To investigate the potential molecular mechanism of NFE2L3, we analyzed the correlation of NFE2L3 with immune molecular mechanisms, constructed PPI network, performed GO analysis and KEGG analysis, and finally explored the biological function of NFE2L3 in gastric cancer cells.

Results: NFE2L3 expression is up-regulated in DSC and has both prognostic and diagnostic value. NFE2L3 correlates with various immune mechanisms, PPI network suggests proteins interacting with NFE2L3, GSEA analysis suggests potential molecular mechanisms for NFE2L3 to play a role in cancer promotion, and in vitro cellular experiments also confirmed the effect of NFE2L3 on the biological function of gastric cancer cells.

Conclusion: Our study confirms the aberrant expression and molecular mechanisms of NFE2L3 in DSC, indicating that NFE2L3 could serve as a novel biomarker for diagnosis and prognosis of DSC.

Keywords: Biomarker; Diagnosis; Digestive system cancers; NFE2L3; Prognosis.

Fig. 1

Expression level of NFE2L3 in pan cancer. A NFE2L3 is expressed at higher levels in pan-cancer unpaired tissues than in paracancerous tissues; B NFE2L3 is expressed at higher levels in pan-cancer paired tissues than in paracancerous tissues; C Expression levels of NFE2L3 in different cell lines from HPA dataset; D NFE2L3 expression in DSC tissues from HPA dataset; E Immunohistochemical staining results of liver cancer and colon cancer suggest that NFE2L3 is expressed at higher levels in tumor tissues than in normal tissues; F Validate the expression level of NFE2L3 in gastric cancer patients

Fig. 2

Relationship between NFE2L3 and MSI or TMB in DSC. A There was a close correlation between NFE2L3 and MSI in STAD, THYM, COAD, DLBC, SKCM, and LUAD; B There was a close correlation between NFE2L3 and TMB in ACC, BLCA, BRCA, LAML, LGG, PAAD, and STAD, COAD, KIRC, and UCEC

Fig. 3

ROC curve of NFE2L3 in DSC. A ROC curve of NFE2L3 in CHOL; B ROC curve of NFE2L3 in COAD; C ROC curve of NFE2L3 in ESCA; D ROC curve of NFE2L3 in PAAD; E ROC curve of NFE2L3 in LIHC; F ROC curve of NFE2L3 in READ; G ROC curve of NFE2L3 in STAD

Fig. 4

Prognostic value of NFE2L3 in DSC. A The overall survival is lower among PAAD patients with high-expression levels of NFE2L3; B The progress-free interval is lower among PAAD patients with high-expression levels of NFE2L3; C The disease-specific survival is lower among PAAD patients with high-expression levels of NFE2L3; D The progress-free interval rate is lower among LIHC patients with high-expression levels of NFE2L3

Fig. 5

NFE2L3 expression in different immune subtypes. A Expression level of NFE2L3 of immune subtypes of PAAD; B Expression level of NFE2L3 of immune subtypes of READ; C Expression level of NFE2L3 of immune subtypes of LIHC; D Expression level of NFE2L3 of immune subtypes of STAD; E Expression level of NFE2L3 of immune subtypes of ESCA; F Expression level of NFE2L3 of immune subtypes of CHOL; G Expression level of NFE2L3 of immune subtypes of COAD

Fig. 6

NFE2L3 expression level in different molecular subtypes. A In COAD, NFE2L3 expresses in four different molecular subtypes; B In ESCA, NFE2L3 expresses in CIN and ESCC; C In READ, NFE2L3 expresses in iCluster1, iCluster2, and iCluster3; D In LIHC, NFE2L3 expresses in four different molecular subtypes; E In STAD, NFE2L3 expresses in four different molecular subtypes

Fig. 7

NFE2L3 expression in different immune cell infiltration. A In COAD, NFE2L3 is expressed in Tregs and CD4 memory cells; B In ESCA, NFE2L3 is expressed in two type immune cells; C In READ, NFE2L3 is expressed in CD4 memory cells; D In LIHC, NFE2L3 is expressed in four type immune cells; E In STAD, NFE2L3 is expressed in six type immune cells

Fig. 8

The relationships between NFE2L3 and immune-related genes or chemokine receptors. A Correlation between NFE2L3 and immune-related genes; B Correlation between NFE2L3 and Chemokine receptors

Fig. 9

GO and KEGG analysis of proteins that interact with NFE2L3. A Proteins interact with NFE2L3; B Go analysis of interacting proteins; C KEGG analysis of interacting proteins

Fig. 10

The biological function of NFE2L3 in gastric cancer. A The expression levels of NFE2L3 in cell lines; B Verification of knockdown efficiency of NFE2L3 in HGC-27; C Verification of overexpression efficiency of NFE2L3 in AGS; D The proliferation ability of NFE2L3 in HGC-27; E The proliferation ability of NFE2L3 in AGS; F The migration ability of NFE2L3 in HGC-27; G The migration ability of NFE2L3 in AGS