Dissecting the expression landscape of mitochondrial genes in lung squamous cell carcinoma and lung adenocarcinoma.

Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the two major subtypes of lung cancer. To explore mitochondrial respiratory gene expression profiles in LUSC and LUAD, RNA sequencing data from The Cancer Genome Atlas was used for comprehensive analyses to establish the molecular characteristics of LUSC and LUAD. To elucidate expression profiles, subtypes were defined using unsupervised clustering of mitochondrial gene expression data. Differences in nuclear gene expression levels, signaling pathways and tumor microenvironments between subtypes were investigated. The analysis revealed that mitochondrial respiratory genes were generally expressed at lower levels in tumor tissues compared with matched control tissues. The expression of mitochondrially encoded NADH dehydrogenase 5 or 6 was associated with tumor progression in LUAD and LUSC. Patients were clustered into three subgroups based on the expression profile of 13 mitochondrial protein-encoding genes, and patients in Cluster 3 exhibited poor survival rates compared with patients from Cluster 1. Furthermore, this association was also observed in another independent data set. Further analyses of the expression of nuclear-encoded genes in the three clusters revealed the enrichment of several cancer-associated signaling pathways in Cluster 3, particularly the apoptotic signaling pathway, suggesting a potential association between the decreased expression of mitochondrial DNA genes and increased tumor aggressiveness. Furthermore, the analyses of immune cell compositions in the tumor microenvironment detected a significant increase in the proportion of CD4+ T cells and a decrease in the proportion of macrophages in LUAD compared with LUSC (P=0.0000104 and P=0.0000105, respectively). In conclusion, the present study revealed an association between the expression patterns of mitochondrial-encoded genes and lung cancer, which may contribute to novel therapeutic strategies for patients with LUSC and LUAD.