Molecular Mechanisms and Clinical Outcomes of Tobacco-Associated Pathologies: A Comparative Review of GPI Transamidase Dysregulation in Head and Neck Squamous Cell Carcinoma and Hemodynamic Prognosis in Abdominal Aortic Aneurysm

Abstract

Background: Tobacco consumption remains a pervasive global health challenge, driving distinct pathologies across physiological systems. This study examines two divergent consequences of systemic tobacco exposure: the molecular upregulation of Glycosylphosphatidylinositol (GPI) transamidase in Head and Neck Squamous Cell Carcinoma (HNSCC) and the hemodynamic failure associated with Abdominal Aortic Aneurysm (AAA).

Methods: A comprehensive review was conducted analyzing genomic data regarding GPI biosynthesis subunits (PIG-U, GPAA1) in HNSCC and clinical outcomes data for AAA screening and repair. Data sources included The Cancer Genome Atlas (TCGA), MIMIC-IV databases, and recent randomized trials comparing endovascular versus open repair.

Results: In HNSCC, overexpression of the PIG-U subunit acts as a critical oncogene, facilitating the anchoring of proteins that drive cellular proliferation and immune evasion within the tumor microenvironment. Tobacco smoke was found to specifically activate protein association and tyrosine phosphorylation of GPI-transamidase subunits. Conversely, in AAA, mortality remains high despite advances in screening; however, updated US Preventive Services Task Force guidelines and predictive scoring systems like the Glasgow Aneurysm Score have improved risk stratification. Endovascular repair continues to show survival benefits over open repair in ruptured cases.

Conclusion: While HNSCC requires a molecular approach targeting GPI-anchored protein pathways and immunomodulation, AAA management relies on early detection and precise surgical intervention. Understanding these distinct pathways highlights the multifaceted impact of tobacco and underscores the need for organ-specific therapeutic strategies.

Keywords:

Head and Neck Squamous Cell Carcinoma, GPI Transamidase, Abdominal Aortic Aneurysm

References

Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024, 74:229-263.

Ruffin AT, Li H, Vujanovic L, Zandberg DP, Ferris RL, Bruno TC: Improving head and neck cancer therapies by immunomodulation of the tumour microenvironment. Nat Rev Cancer 2023, 23:173-188.

Miyauchi S, Kim SS, Pang J, Gold KA, Gutkind JS, Califano JA, Mell LK, Cohen EEW, Sharabi AB: Immune Modulation of Head and Neck Squamous Cell Carcinoma and the Tumor Microenvironment by Conventional Therapeutics. Clin Cancer Res 2019, 25:4211-4223.

Cancer Genome Atlas N: Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015, 517:576-582.

Hong Y, Ohishi K, Kang JY, Tanaka S, Inoue N, Nishimura J, Maeda Y, Kinoshita T: Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that attaches GPI-anchors to proteins. Mol Biol Cell 2003, 14:1780-1789.

Kinoshita T, Fujita M: Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling. J Lipid Res 2016, 57:6-24.

Kinoshita T: Biosynthesis and biology of mammalian GPI-anchored proteins. Open Biol 2020, 10:190290.

Xu Y, Li T, Zhou Z, Hong J, Chao Y, Zhu Z, Zhang Y, Qu Q, Li D: Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis. Nat Commun 2023, 14:5520.

Li D: Structure and Function of the Glycosylphosphatidylinositol Transamidase, a Transmembrane Complex Catalyzing GPI Anchoring of Proteins. Subcell Biochem 2024, 104:425-458.

Gamage DG, Hendrickson TL: GPI transamidase and GPI anchored proteins: oncogenes and biomarkers for cancer. Crit Rev Biochem Mol Biol 2013, 48:446-464.

Guo Z, Linn JF, Wu G, Anzick SL, Eisenberger CF, Halachmi S, Cohen Y, Fomenkov A, Hoque MO, Okami K et al: CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer. Nat Med 2004, 10:374-381.

Jiang WW, Zahurak M, Zhou ZT, Park HL, Guo ZM, Wu GJ, Sidransky D, Trink B, Califano JA: Alterations of GPI transamidase subunits in head and neck squamous carcinoma. Mol Cancer 2007, 6:74.

Yiping Huang JKN, Barry Trink, Edward A. Ratovitski: Tobacco Smoke Activates Protein Association and Tyrosine Phosphorylation of the GPI-Transamidase Complex Subunits in Human Cancers. Journal of Epithelial Biology & Pharmacology 2009, 2:14-22.

Zhang XX, Ni B, Li Q, Hu LP, Jiang SH, Li RK, Tian GA, Zhu LL, Li J, Zhang XL et al: GPAA1 promotes gastric cancer progression via upregulation of GPI-anchored protein and enhancement of ERBB signalling pathway. J Exp Clin Cancer Res 2019, 38:214.

Guirguis-Blake JM, Beil TL, Senger CA, Coppola EL. Primary Care Screening for Abdominal Aortic Aneurysm: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2019;322(22):2219. doi:10.1001/jama.2019.17021

US Preventive Services Task Force, Owens DK, Davidson KW, et al. Screening for Abdominal Aortic Aneurysm: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322(22):2211. doi:10.1001/jama.2019.18928

Reimerink JJ, Van Der Laan MJ, Koelemay MJ, Balm R, Legemate DA. Systematic review and meta-analysis of population-based mortality from ruptured abdominal aortic aneurysm. British Journal of Surgery. 2013;100(11):1405-1413. doi:10.1002/bjs.9235

Sweeting MJ, Balm R, Desgranges P, et al. Individual-patient meta-analysis of three randomized trials comparing endovascular versus open repair for ruptured abdominal aortic aneurysm. British Journal of Surgery. 2015;102(10):1229-1239. doi:10.1002/bjs.9852

Karthikesalingam A, Holt PJ, Vidal-Diez A, et al. Mortality from ruptured abdominal aortic aneurysms: clinical lessons from a comparison of outcomes in England and the USA. The Lancet. 2014;383(9921):963-969. doi:10.1016/S0140-6736(14)60109-4

Verhoeven EL, Kapma MR, Groen H, et al. Mortality of ruptured abdominal aortic aneurysm treated with open or endovascular repair. Journal of Vascular Surgery. 2008;48(6):1396-1400. doi:10.1016/j.jvs.2008.07.054

Chen Q, Chen Q, Ye Y, Wu R, Wang S, Yao C. Characteristics and Prognosis of Abdominal or Thoracic Aortic Aneurysm Patients Admitted to Intensive Care Units After Surgical Treatment: A Multicenter Retrospective Observational Study. IJGM. 2021;Volume 14:475-486. doi:10.2147/IJGM.S296125

Wang H, Wu S, Pan D, et al. Comparison of different intensive care scoring systems and Glasgow Aneurysm score for aortic aneurysm in predicting 28-day mortality: a retrospective cohort study from MIMIC-IV database. BMC Cardiovasc Disord. 2024;24(1):513. doi:10.1186/1s12872-024-04184-4

Swerdlow NJ, Wu WW, Schermerhorn ML. Open and Endovascular Management of Aortic Aneurysms. Circulation Research. 2019;124(4):647-661. doi:10.1161/CIRCRESAHA.118.313186