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Toxicogenomic Characterization of Common Genes and Signaling Pathways Associated with Multiple Toxic Metal(loid)s in
Katarina Živančević1, Kıvanç Kök2,3
1Department of General Physiology and Biophysics, Center for Laser Microscopy, Institute of Physiology and Biochemistry "Ivan Djaja", Faculty of Biology, University of Belgrade, Studentski trg 16, 11158 Belgrade, Serbia.
Abstract:
Background/Objectives: This study aimed to identify common target genes, molecular interaction networks, and signaling pathways shared across the investigated toxic metal(loid)s-lead (Pb), cadmium (Cd), methylmercury compounds (MMC), arsenic (As), nickel (Ni), and hexavalent chromium (Cr(VI))-and associated with lung cancer overall, non-small-cell lung cancer (NSCLC), and small-cell lung cancer (SCLC). Methods: The Comparative Toxicogenomics Database (CTD) was used to identify associated genes, GeneMANIA to characterize molecular interaction networks, and ToppFun for pathway enrichment analysis. Results: Two common genes (MTOR and TP53) were identified for SCLC, eight for NSCLC (CAT, CCNB1, MTOR, NQO1, SOD2, STAT3, TP53, and VEGFA), and eighteen for lung cancer overall. Gene network analysis revealed predominantly physical interactions in SCLC, pathway interactions in NSCLC, and co-expression in lung cancer overall. Several toxic metal(loid)s exhibited concordant effects on TP53, VEGFA, HMOX1, and IL6 expression. TP53 was the only gene common to all investigated toxic metal(loid)s and lung cancer categories. Pathway enrichment identified PI3K-AKT-mTOR signaling in both SCLC and NSCLC, VEGF signaling in NSCLC, and MAPK, interleukin, and macrophage-stimulating protein (MSP) signaling in lung cancer overall. Conclusions: The identified genes and pathways suggest molecular mechanisms potentially relevant to the association between exposure to the investigated toxic metal(loid)s and lung carcinogenesis, particularly those related to cell survival, inflammation, oxidative stress, and angiogenesis. TP53 may represent a common molecular link warranting further investigation. The identified pathways represent candidate biomarkers and mechanistic targets, highlighting the biological heterogeneity of lung cancer and the importance of subtype-specific analyses.
Insights
Toxic metal(loid)s like lead and arsenic may contribute to lung cancer by affecting common genes such as TP53. This study identifies shared molecular pathways across lung cancer subtypes, suggesting potential therapeutic targets and biomarkers for lung carcinogenesis.
Area of Science:
- Toxicology
- Genomics
- Oncology
Background:
- Exposure to toxic metal(loid)s is linked to lung cancer.
- Understanding shared molecular mechanisms across lung cancer subtypes (NSCLC, SCLC) is crucial.
Purpose of the Study:
- Identify common genes, networks, and pathways shared by toxic metal(loid)s (Pb, Cd, MMC, As, Ni, Cr(VI)) and lung cancer.
- Investigate associations with overall lung cancer, NSCLC, and SCLC.
Main Methods:
- Utilized the Comparative Toxicogenomics Database (CTD) for gene identification.
- Employed GeneMANIA for molecular interaction network analysis.
- Conducted pathway enrichment analysis using ToppFun.
Main Results:
- Identified common genes including TP53 (across all), MTOR, and VEGFA.
- TP53 was the sole gene common to all metal(loid)s and lung cancer types.
- Discovered shared pathways like PI3K-AKT-mTOR, VEGF, MAPK, and interleukin signaling.
Conclusions:
- Identified genes and pathways suggest mechanisms in cell survival, inflammation, oxidative stress, and angiogenesis.
- TP53 is a potential common molecular link for toxic metal(loid)-induced lung carcinogenesis.
- Findings highlight lung cancer heterogeneity and the need for subtype-specific analysis.
