Clinicopathological significance of unraveling mitochondrial pathway alterations in non-small-cell lung cancer.
Kate L HertweckKunwar S VikramdeoJose N GaleasStephen M MarbutParamahansa PramanikFurhan YunusSeema SinghAjay P SinghSantanu DasguptaPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2023)
Early detection, accurate monitoring, and therapeutics are major problems in non-small-cell lung cancer (NSCLC) patients. We identified genomic copy number variation of a unique panel of 40 mitochondria-targeted genes in NSCLCs (GEOGSE #29365). Validation of mRNA expression of these molecules revealed an altered panel of 34 genes in lung adenocarcinomas (LUAD) and 36 genes in lung squamous cell carcinomas (LUSC). In the LUAD subtype (n = 533), we identified 29 upregulated and 5 downregulated genes, while in the LUSC subtype (n = 502), a panel of 30 upregulated and 6 downregulated genes were discovered. The majority of these genes are associated with mitochondrial protein transport, ferroptosis, calcium signaling, metabolism, OXPHOS function, TCA cycle, apoptosis, and MARylation. Altered mRNA expression of SLC25A4, ACSF2, MACROD1, and GCAT was associated with poor survival of the NSCLC patients. Progressive loss of SLC25A4 protein expression was confirmed in NSCLC tissues (n = 59), predicting poor survival of the patients. Forced overexpression of SLC25A4 in two LUAD cell lines inhibited their growth, viability, and migration. A significant association of the altered mitochondrial pathway genes with LC subtype-specific classical molecular signatures was observed, implicating the existence of nuclear-mitochondrial cross-talks. Key alteration signatures shared between LUAD and LUSC subtypes including SLC25A4, ACSF2, MACROD1, MDH2, LONP1, MTHFD2, and CA5A could be helpful in developing new biomarkers and therapeutics.
Keyphrases
- genome wide
- end stage renal disease
- copy number
- ejection fraction
- chronic kidney disease
- oxidative stress
- small cell lung cancer
- newly diagnosed
- prognostic factors
- squamous cell
- cell death
- multiple sclerosis
- bioinformatics analysis
- genome wide identification
- small molecule
- mitochondrial dna
- cell proliferation
- signaling pathway
- high resolution
- free survival
- high grade
- reactive oxygen species
- drug delivery