Transcriptome analysis reveals gender-specific differences in overall metabolic response of male and female patients in lung adenocarcinoma

Abstract

Background Evidence from multiple studies suggests metabolic abnormalities play an important role in lung cancer. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. The present study aimed to explore differences in the global metabolic response between male and female patients in LUAD and to identify the metabolic genes associated with lung cancer susceptibility. Methods Transcriptome and clinical LUAD data were acquired from The Cancer Genome Atlas (TCGA) database. Information on metabolic genes and metabolic subsystems were collected from the Recon3D human metabolic model. Two validation datasets (GSE68465 and GSE72094) were downloaded from the Gene Expression Omnibus (GEO) database. Differential expression analysis, gene set enrichment analysis and protein-protein interaction networks were used to identified key metabolic pathways and genes. Functional experiments were used to verify the effects of genes on proliferation, migration, and invasion in lung cancer cells in vitro. Results Samples of tumors and adjacent non-tumor tissue from both male and female patients exhibited distinct global patterns of gene expression. In addition, we found large differences in methionine and cysteine metabolism, pyruvate metabolism, cholesterol metabolism, nicotinamide adenine dinucleotide (NAD) metabolism, and nuclear transport between male and female LUAD patients. We identified 34 metabolic genes associated with lung cancer

Genome-Wide Sex and Gender Differences in Cancer

“…In hepatocellular carcinoma, sex differences are also found in several signaling pathways that are targets for anticancer therapies: PPAR is enriched for genes overexpressed in females, while PI3K, PI3K/AKT, EGFR, IL-2 are enriched for genes overexpressed in males (118). Other studies confirm that evaluating sex differential gene expression can help understand sex differences in cancer etiology (118,123), distribution of molecular subtypes (124,125), and outcomes (126)(127)(128)(129). Sex differences in gene expression was also used to predict drug sensitivity in each sex (130).…”

The Diverse Roles of TAO Kinases in Health and Diseases

“…TAOK1 was found to be overexpressed in lung cancer tissues compared to normal lung tissues in a study using in situ hybridization to search for alterations of serine/threonine kinase expression in cancers [ 52 ]. However, in a transcriptome assay of lung adenocarcinoma, TAOK2 was found to be downregulated in tumor tissues compared to the normal lung [ 56 ]. Such results may indicate the opposite roles of TAOK1 and TAOK2 in lung tumorigenesis.…”

Functional Signatures in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Sex-Based Differences in Transcriptomic Studies

“…To the best of our knowledge, only four studies have attempted to address the functional alterations caused by lung adenocarcinoma in both male and female patients—those by Shi et al [ 16 ], which considered female patients, Araujo et al [ 15 ], Yuan et al [ 17 ], and Li et al [ 18 ]. Shi et al [ 16 ] integrated samples from two datasets for a differential expression analysis followed by a functional enrichment analysis, whereas Araujo et al [ 15 ] independently processed six datasets and jointly analyzed their results.…”

“…Yuan et al [ 17 ] compared male and female patients with various cancer types (including lung adenocarcinoma) using the TCGA dataset, but did not include control samples in the statistical comparison. Li et al [ 18 ] evaluated the differences in lung adenocarcinoma by focusing only on metabolic pathways. By including both male and female patients and controls in our gene expression comparison, in contrast with the analysis performed by Shi et al [ 16 ] and Yuan et al [ 17 ], we have effectively unveiled sex-based differences occurring in lung adenocarcinoma.…”

“…Interestingly, Wheatley-Price et al demonstrated a more pronounced survival rate difference between male and female lung adenocarcinoma patients when compared to other tumor types [ 7 ]. The molecular causes underlying such sex-biased patterns remain largely unknown, as limited efforts have been made for lung adenocarcinoma, with few studies considering this differential perspective [ 15 , 16 , 17 , 18 ]. These limitations can be partially addressed through meta-analysis, a robust methodology that combines information from related but independent studies to derive results with increased statistical power and precision [ 19 , 20 ].…”