LRMP Associates With Immune Infiltrates and Acts as a Prognostic Biomarker in Lung Adenocarcinoma

Abstract

Background: Lymphoid-restricted membrane protein (LRMP) is an endoplasmic reticulum-associated protein that is expressed in a developmentally regulated manner in both B and T cell lineages. However, the role of LRMP in the growth, prognosis and immune infiltration in lung adenocarcinoma (LUAD) remains unclear.Method: The expression levels of LRMP mRNA in tumor and normal tissues were analyzed using Tumor Immune Estimation Resource 2.0 (TIMER 2.0) and Gene Expression Profiling Interactive Analysis 2 (GEPIA 2). LRMP protein expression was examined using the Human Protein Atlas. In vitro experiments, including qRT-PCR Western blot and immunohistochemistry staining were also performed to investigate LRMP expression. GEPIA2 and Kaplan-Meier plotter databases were used to analyze the clinical prognostic significance of LRMP. To further confirm the underlying function of LRMP, the data were analyzed using gene set enrichment analysis. Moreover, we also constructed plasmids to overexpress LRMP and explored the effect of LRMP in A549 cell line. Additionally, Tumor Immune single-cell Hub was used to investigate the distribution of LRMP in the LUAD immune microenvironment; TIMER and CIBERSORT were used to investigate the relationships among LRMP, LRMP co-expressed genes, and tumor-infiltrating immune cells; Finally, the correlations between LRMP and immune checkpoints were analyzed using TIMER 2.0.Results: The expression of LRMP was significantly lower in LUAD tissues and cell lines. High LRMP expression is associated with a better prognosis in patients with LUAD. In vitro experimental studies demonstrated that overexpression of LRMP could decrease the proliferation, migration and invasion in A549 cells, and downregulated multiple oncogenic signaling pathways, including p-STAT3, p-PI3K-p-AKT, p-MEK and EMT pathways. GSEA results showed that immuno-related and cell adhesion pathways were enriched in samples with high LRMP expression. LRMP and its co-expressed genes were positively correlated with various tumor-infiltrating immune cells and their markers. Additionally, LRMP positively correlated with immune checkpoints.Conclusions: Our data suggest that LRMP may act as a tumor suppressor gene and indicates a better prognosis. Moreover, LRMP is associated with immune infiltrates which may be involved in immunotherapy response in LUAD. Further studies are needed to validate these findings.

Novel Functional Features of cGMP Substrate Proteins IRAG1 and IRAG2

“…Thereby, no obvious differences between normal lung and lung adenocarcinoma tissue in IRAG2 expression levels were observed [ 107 , 108 , 109 ]. This, however, is in contrast to the data of Jin et al, who detected a lower IRAG2 gene and protein expression in lung adenocarcinoma tissue [ 104 ]. It is also shown that an IRAG2 Pro537Leu nonconservative variation was linked with an inflammatory response in the lungs of several mouse strains [ 110 ].…”

“…Additionally, high IRAG2 expression correlated with an upregulation of immune checkpoints. Hence, IRAG2 could also be involved in the immunotherapy response of lung adenocarcinoma patients using checkpoint inhibitors [ 104 ].…”

“…Lower IRAG2 expression was detected in many other solid cancers, e.g., breast invasive carcinoma, colon adenocarcinoma, glioblastoma multiforme, kidney chromophobe, kidney renal papillary cell carcinoma, prostate adenocarcinoma, rectum adenocarcinoma, and uterine corpus endometrial carcinoma [ 104 ]. This suggests a role for IRAG2 overexpression also in other solid cancers.…”

“…In animal studies, IRAG2 polymorphisms increased the risk of lung tumors. In humans, the analysis revealed no significant association of these SNPs with enhanced lung cancer risk [ 104 , 107 , 108 , 109 ]. However, in patients with age at tumor onset ≤65 years, survival rates of patients carrying either the Leu/Leu or the Val/Leu genotype differed significantly from those with the Val/Val genotype.…”

“…3.7.) [ 104 ]. The Ser197Cys SNP, however, showed no effect on the survival of lung cancer patients [ 109 ].…”