Investigating the role of TIMM8B in lung adenocarcinoma: Expression patterns, prognostic value, and therapeutic implications

Introduction: Translocase of inner mitochondrial membrane 8 homolog B (TIMM8B) is crucial for mitochondrial function, but its role in lung adenocarcinoma (LUAD) remains underexplored.
Objective: This study investigates TIMM8B expression patterns, prognostic value, and potential therapeutic implications in LUAD.
Methods: The expression and prognostic potential of TIMM8B in LUAD were analyzed using data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression, Gene Expression Omnibus, and Gene Expression Profiling Interactive Analysis 2, with survival analysis performed through Kaplan–Meier plotter. The prognostic value was validated using a LUAD tissue microarray and a nomogram. TIMM8B-related differentially expressed genes were identified using TCGA and LinkedOmics, and were functionally annotated using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Immunological features were assessed using TCGA data through the XCELL and tumor immune dysfunction and exclusion algorithms. Associations among TIMM8B, m6A modification, ferroptosis-related genes, and tumor genetic mutations were analyzed using TCGA data. Drug response correlations were explored using the Genomics of Drug Sensitivity in Cancer and Comparative Toxicogenomics databases. TIMM8B-depleted LUAD cell lines were analyzed using ribonucleic acid sequencing and subjected to cell cycle analysis.
Results: TIMM8B is overexpressed in multiple cancers, including LUAD. High TIMM8B expression correlates with poorer overall survival in LUAD. A nomogram incorporating TIMM8B and pathological tumor-node-metastasis stage showed reliable predictive performance. TIMM8B-related gene analyses suggest roles in cell adhesion, chromosome segregation, and critical cancer pathways. TIMM8B shapes an immunosuppressive tumor microenvironment in LUAD, affecting immune cell infiltration and immunotherapy response. Elevated TIMM8B expression is associated with TP53 mutations and chemotherapy resistance. Knockdown of TIMM8B in H1299 cells downregulates PD-L1, induces G1 phase arrest, and triggers a chemokine (C-C motif) ligand 2-mediated inflammatory response, highlighting roles in cell cycle regulation and inflammatory pathways.
Conclusion: These findings underscore TIMM8B’s multifaceted role in cancer progression and its potential as a prognostic marker and therapeutic target in LUAD.
- Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi: 10.3322/caac.21834
- Suster DI, Mino-Kenudson M. Molecular pathology of primary non-small cell lung cancer. Arch Med Res. 2020;51(8):784-798. doi: 10.1016/j.arcmed.2020.08.004
- Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398(10299):535-554. doi: 10.1016/S0140-6736(21)00312-3
- Chen VW, Ruiz BA, Hsieh MC, Wu XC, Ries LAG, Lewis DR. Analysis of stage and clinical/prognostic factors for lung cancer from SEER registries: AJCC staging and collaborative stage data collection system. Cancer. 2014;120 Suppl 23:3781-3792. doi: 10.1002/cncr.29045
- Chiu HY, Tay EXY, Ong DST, Taneja R. Mitochondrial dysfunction at the center of cancer therapy. Antioxid Redox Signal. 2020;32(5):309-330. doi: 10.1089/ars.2019.7898
- Bauer MF, Hofmann S, Neupert W, Brunner M. Protein translocation into mitochondria: The role of TIM complexes. Trends Cell Biol. 2000;10(1):25-31. doi: 10.1016/s0962-8924(99)01684-0
- Pfanner N, Warscheid B, Wiedemann N. Mitochondrial proteins: From biogenesis to functional networks. Nat Rev Mol Cell Biol. 2019;20(5):267-284. doi: 10.1038/s41580-018-0092-0
- Salhab M, Patani N, Jiang W, Mokbel K. High TIMM17A expression is associated with adverse pathological and clinical outcomes in human breast cancer. Breast Cancer. 2012;19(2):153-160. doi: 10.1007/s12282-010-0228-3
- Cai J, Chen J, Huang L, et al. A TIMM17A regulatory network contributing to breast cancer. Front Genet. 2021;12:658154. doi: 10.3389/fgene.2021.658154
- Zhang Y, Lin L, Wu Y, Bing P, Zhou J, Yu W. Upregulation of TIMM8A is correlated with prognosis and immune regulation in BC. Front Oncol. 2022;12:922178. doi: 10.3389/fonc.2022.922178
- Wang Z, Li S, Xu F, et al. ncRNAs-mediated high expression of TIMM8A correlates with poor prognosis and act as an oncogene in breast cancer. Cancer Cell Int. 2022;22(1):177. doi: 10.1186/s12935-022-02595-x
- Zhu X, Yuan Z, Cheng S, et al. TIMM8A is associated with dysfunction of immune cell in BRCA and UCEC for predicting anti-PD-L1 therapy efficacy. World J Surg Oncol. 2022;20(1):336. doi: 10.1186/s12957-022-02736-6
- Jin H, Kendall E, Freeman TC, Roberts RG, Vetrie DL. The human family of Deafness/Dystonia peptide (DDP) related mitochondrial import proteins. Genomics. 1999;61(3):259-267. doi: 10.1006/geno.1999.5966
- Badenhop RF, Cherian S, Lord RS, Baysal BE, Taschner PE, Schofield PR. Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss. Genes Chromosomes Cancer. 2001;31(3):255-263. doi: 10.1002/gcc.1142
- Hoekstra AS, van den Ende B, Julia XP, et al. Simple and rapid characterization of novel large germline deletions in SDHB, SDHC and SDHD-related paraganglioma. Clin Genet. 2017;91(4):536-544. doi: 10.1111/cge.12843
- Zhang J, Zhou X, Zhu C, et al. Wholegenome identification and systematic analysis of lncRNAmRNA coexpression profiles in patients with cutaneous basal cell carcinoma. Mol Med Rep. 2021;24(3):631. doi: 10.3892/mmr.2021.12270
- Del Puerto-Nevado L, Santiago-Hernandez A, Solanes-Casado S, et al. Diabetes-mediated promotion of colon mucosa carcinogenesis is associated with mitochondrial dysfunction. Mol Oncol. 2019;13(9):1887-1897. doi: 10.1002/1878-0261.12531
- Jiang P, Gu S, Pan D, et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018;24(10):1550-1558. doi: 10.1038/s41591-018-0136-1
- Li Y, Xiao J, Bai J, et al. Molecular characterization and clinical relevance of m(6)A regulators across 33 cancer types. Mol Cancer. 2019;18(1):137. doi: 10.1186/s12943-019-1066-3
- Liu Z, Zhao Q, Zuo ZX, et al. Systematic analysis of the aberrances and functional implications of ferroptosis in cancer. iScience. 2020;23(7):101302. doi: 10.1016/j.isci.2020.101302
- Malta TM, Sokolov A, Gentles AJ, et al. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell. 2018;173(2):338-354.e15. doi: 10.1016/j.cell.2018.03.034
- Morris GM, Huey R, Olson AJ. Using AutoDock for ligand-receptor docking. Curr Protoc Bioinformatics. 2008;Chapter 8:Unit 8 14. doi: 10.1002/0471250953.bi0814s24
- Wang Y, Bryant SH, Cheng T, et al. PubChem BioAssay: 2017 update. Nucleic Acids Res. 2017;45(D1):D955-D963. doi: 10.1093/nar/gkw1118
- Wang K, Zhang Y, Ao M, Luo H, Mao W, Li B. Multi-omics analysis defines a cuproptosis-related prognostic model for ovarian cancer: Implication of WASF2 in cuproptosis resistance. Life Sci. 2023;332:122081. doi: 10.1016/j.lfs.2023.122081
- Zhang L, Shi X, Zhang L, Mi Y, Zuo L, Gao S. A first-in-class TIMM44 blocker inhibits bladder cancer cell growth. Cell Death Dis. 2024;15(3):204. doi: 10.1038/s41419-024-06585-x
- Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ. 2022;29(5):946-960. doi: 10.1038/s41418-022-00988-z
- Voskarides K, Giannopoulou N. The role of TP53 in adaptation and evolution. Cells. 2023;12(3):512. doi: 10.3390/cells12030512
- Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227-242. doi: 10.1038/nri3405
- Speiser DE, Chijioke O, Schaeuble K, Munz C. CD4(+) T cells in cancer. Nat Cancer. 2023;4(3):317-329. doi: 10.1038/s43018-023-00521-2
- Park S, Ock CY, Kim H, et al. Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as complementary biomarker for immune checkpoint inhibition in non-small-cell lung cancer. J Clin Oncol. 2022;40(17):1916-1928. doi: 10.1200/JCO.21.02010
- Kearney CJ, Vervoort SJ, Hogg SJ, et al. Tumor immune evasion arises through loss of TNF sensitivity. Sci Immunol. 2018;3(23):e aar3451. doi: 10.1126/sciimmunol.aar3451
- Krummel MF, Mahale JN, Uhl LFK, et al. Paracrine costimulation of IFN-γ signaling by integrins modulates CD8 T cell differentiation. Proc Natl Acad Sci U S A. 2018;115(45):11585-11590. doi: 10.1073/pnas.1804556115
- Yang H, Zhang Q, Xu M, et al. CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer. 2020;19(1):41. doi: 10.1186/s12943-020-01165-x