Role of ALOX5 in non-small cell lung cancer: A potential therapeutic target associated with immune cell infiltration.

Abstract

The efficacy of immunotherapy for lung cancer is closely related to immune cell infiltration. Arachidonic acid 5-lipoxygenase (ALOX5) can activate inflammatory responses and trigger various cell death patterns; however, the relevance of ALOX5 to immune cell infiltration in lung cancer is unclear. The expression of ALOX5 in non-small cell lung cancer (NSCLC) is analyzed using an online database to explore the correlation between ALOX5 and immune cell infiltration in NSCLC and its relationship with prognosis. Differences in ALOX5 expression in NSCLC and normal lung tissues were analyzed by online databases such as TIMER, GEPIA and HPA; the UALCAN database was used to reveal the relationship between ALOX5 and clinical features; Kaplan-Meier database was applied to explore the prognostic value of ALOX5; GeneMANIA and String Website was used to explore genes and proteins associated with ALOX5 expression, respectively; the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to analyze ALOX5 differential genes which were picked up through the TCGA database; GSEA software was applied to predict the signal pathways that ALOX5 may be involved in; and the TIMER database was used to analyze the effect of ALOX5 expression on the level of immune cell infiltration. Compared with the normal lung tissues, the ALOX5 expression was low in NSCLC tissues (P<0.05), and which affected the prognosis of lung cancer patients. The expression level of ALOX5 was related to clinical features such as sex, age, metastasis, and pathological staging in NSCLC patients (all P<0.05). The gene interaction network analysis found that the genes interacting with ALOX5 mainly included the genes related to lipid oxidation and pro-inflammatory mediators such as coactosin like protein 1 (COTL1), leukotriene C4 synthase (LTC4S), and prostaglandin endoperoxide synthase 2 (PTGS2), and the protein-protein interaction analysis results were consistent. GO and KEGG analysis found that ALOX5 was involved in the biological process of activation of immune cell function and was involved in immune response function pathways. The GSEA analysis showed that ALOX5 may activate immune responses and mediate immune-related prognosis by affecting the cytokine-cytokine receptor interactions, natural killer-mediated cytotoxicity, and T cell receptor signaling pathways. The ALOX5 mRNA expressions in lung adenocarcinoma and lung squamous cell carcinoma were positively correlated with the tumor infiltration immune cells (B cells, CD8+ T cells, CD4+ T cells, etc.) (all P<0.05), and the ALOX5 mRNA expression was positively correlated with the expression of classic T cell immune checkpoint inhibitor genes (P<0.001). The ALOX5 gene expression in NSCLC is significantly downregulated, and which can affect NSCLC prognosis and immune cell infiltration levels. ALOX5 gene may be a potential biomarker of NSCLC prognosis associated with immune cell infiltration.