Upregulated Acute Systemic Inflammation-Related Genes based on Endotoxin Exposure Provide “Survival Benefit” or Create “High Risk of Death” in Leukaemia and Colon Cancer

Year 2024, , 152 - 159, 19.12.2024

Gizem Ayna Duran

https://doi.org/10.26650/EurJBiol.2024.1459040

Abstract

Objective: Although endotoxin exposure has been shown to trigger innate immune responses and promote cancer, it has also been shown to prevent cancer formation. In our study, survival analysis was performed to determine whether the upregulated genes triggered by endotoxins have hazardous effects on cancers or provide a survival benefit.

Materials and Methods: Gene intensity values of control and bacterial endotoxin-administered individuals were obtained from the Gene Expression Omnibus database. Using the R “Linear Models for Microarray Data” package, differentially expressed gene analyses were conducted to determine genes that differ between healthy and bacterial endotoxin-administered samples. “ShinyGo 0.80” web-based tool was used to determine the disease types indicated by these genes. The “Kaplan-Meier Plotter” web-based tool was used to conduct survival analysis.

Results: Genes that create an innate immune response to bacterial endotoxin exposure and are upregulated differently than in individuals without exposure were identified. According to gene enrichment analyses, the two main types of cancer identified were leukaemia/lymoma and colon cancer. We detected that MLF1, STAT5B, and BCL3 genes led to poor survival; however, the ARHGAP26 gene was protective for acute myeloid leukaemia patients. In the case of colon cancer, SMAD7 and TLR2 genes were determined as leading to “high risk of death”.

Conclusion: Once the systemic inflammation-related genes identified in our study are confirmed through laboratory experiments in samples taken from solid tissue in the case of colon cancer and at the level of genes obtained from blood samples in leukemias, genetically targeted treatments will also be possible.

Keywords

Cancer, Endotoxin, Systemic inflammation, Bioinformatics, Survival

References

• Heine H, Rietschel ET, Ulmer AJ. The biology of endotoxin. Mol Biotechnol. 2001;19:279-296. google scholar
• Kellum JA, Ronco C. The role of endotoxin in septic shock. Crit Care. 2023;27: 400. doi: 10.1186/s13054-023-04690-5 google scholar
• Vogel SN, Hogan MM. Role of cytokines in endotoxin mediated host responses. In: Oppenheim JJ, Shevach EM, Eds. Immuno-physiology. The roles of cells and cytokines in immunity and inflammation. 1990; p.238-258. google scholar
• Cao H. Bacterial endotoxin lipopolysaccharides regulate gene expression in human colon cancer cells. BMC Res Notes. 2023;13:16(1):216. doi: 10.1186/s13104-023-06506-9 google scholar
• Wu X, Qian S, Zhang J, et al. Lipopolysaccharide promotes metastasis via acceleration of glycolysis by the nuclear factor-xB/snail/hexokinase3 signaling axis in colorectal cancer. Cancer Metab. 2021;12:9(1):23. doi: 10.1186/s40170-021-00260-x google scholar
• Sun J, Chen F, Wu G. Potential effects of gut microbiota on host cancers: Focus on immunity, DNA damage, cellular pathways, and anticancer therapy. ISME J. 2023;17(10):1535-1551. google scholar
• Roberti MP, Yonekura S, Duong CPM, et al. Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer. Nat Med. 2020;26(6):919-931. google scholar
• Goodwin AC, Destefano Shields CE, Wu S, et al. Polyamine catabolism contributes to enterotoxigenic Bacteroides frag-ilis induced colon tumorigenesis. Proc Natl Acad Sci USA. 2011;108:15354-15359. google scholar
• Mager LF, Burkhard R, Pett N, et al. Microbiome-derived ino-sine modulates response to checkpoint inhibitor immunotherapy. Science. 2020;18:369(6510):1481-1489. google scholar
• Wang R, Yang X, Liu J, et al. Gut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate. Nat Commun. 2022;9:13(1):2522. doi: 10.1038/s41467-022-30240-8 google scholar
• Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15(11):e493-503. doi: 10.1016/S1470-2045(14)70263-3. google scholar
• Dolan RD, Laird BJA, Horgan PG, McMillan DC. The prognos-tic value of the systemic inflammatory response in randomised clinical trials in cancer: A systematic review. Crit Rev Oncol Hematol. 2018;132:130-137. google scholar
• N0st TH, Alcala K, Urbarova I, Byrne KS, et al. Systemic in-flammation markers and cancer incidence in the UK Biobank. Eur J Epidemiol. 2021;36(8):841-848. google scholar
• Zhou Q, Su S, You W, Wang T, Ren T, Zhu L. Systemic in-flammation response index as a prognostic marker in cancer patients: A systematic review and meta-analysis of 38 cohorts. Dose Response. 2021;15:19(4):1-14. google scholar
• Calvano SE, Xiao W, Richards DR, et al. A network-based analysis of systemic inflammation in humans. Nature. 2005;13:437(7061):1032-1037. google scholar
• Foteinou PT, Calvano SE, Lowry SF, Androulakis IP. Multiscale model for the assessment of autonomic dysfunction in human endotoxemia. Physiol Genomics. 2010;42(1):5-19. google scholar
• Foteinou PT, Calvano SE, Lowry SF, Androulakis IP. In sil-ico simulation of corticosteroids effect on an NFkB- dependent physicochemical model of systemic inflammation. PLoS One. 2009;4(3):e4706. doi: 10.1371/journal.pone.0004706 google scholar
• Nguyen TT, Calvano SE, Lowry SF, Androulakis IP. An agent-based model of cellular dynamics and circadian variability in human endotoxemia. PLoS One. 2013;8(1):e55550. doi: 10.1371/journal.pone.0055550 google scholar
• Ge SX, Jung D, Yao R. ShinyGO: A graphical gene-set en-richment tool for animals and plants. Bioinformatics. 2020; 36:2628-2629. google scholar
• Kovacs SA, Fekete JT, Gyorffy B. Predictive biomarkers of immunotherapy response with pharmacological applications in solid tumors. Acta Pharmacol Sin. 2023;44(9):1879-1889. google scholar
• Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021;19(1):55-71. google scholar
• Rinninella E, Raoul P, Cintoni M, et al. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms. 2019;10;7(1):14. doi: 10.3390/microorganisms7010014 google scholar
• Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;16;474(11):1823-1836. google scholar
• Liu Y, Baba Y, Ishimoto T, et al. Gut microbiome in gastrointesti-nal cancer: A friend or foe? Int J Biol Sci. 2022;21;18(10):4101-4117. google scholar
• Troncone E, Monteleone G. Smad7 and colorectal carcinogene-sis: A double-edged sword. Cancers (Basel). 2019;1:11(5):612. doi: 10.3390/cancers11050612 google scholar
• Wang L, Tang L, Feng Y, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice. Gut. 2020;69(11):1988-1997. google scholar
• Wang R, Yang X, Liu J, et al. Gut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate. Nat Commun. 2022;9;13(1):2522. doi: 10.1038/s41467-022-30240-8 google scholar
• Vicente-Duenas C, Janssen S, Oldenburg M, et al. An intact gut microbiome protects genetically predisposed mice against leukemia. Blood. 2020;29;136(18):2003-2017. google scholar
• Niu Y, Yang X, Chen Y, et al. BCL3 expression is a potential prognostic and predictive biomarker in acute myeloid leukemia of FAB subtype M2. Pathol Oncol Res. 2019; 25(2):541-548. google scholar
• Almajali B, Johan MF, Al-Wajeeh AS, et al. Gene ex-pression profiling and protein analysis reveal suppression of the C-Myc oncogene and inhibition JAK/STAT and PI3K/AKT/mTOR signaling by thymoquinone in acute myeloid leukemia cells. Pharmaceuticals (Basel). 2022; 3;15(3):307. doi: 10.3390/ph15030307 google scholar
• Wingelhofer B, Maurer B, Heyes EC, et al. Pharmacologic in-hibition of STAT5 in acute myeloid leukemia. Leukemia. 2018; 32(5):1135-1146. google scholar
• Li Z, Yang Y, Wu K, et al. Myeloid leukemia factor 1: A "double-edged sword" in health and disease. Front Oncol. 2023;13:1124978. doi: 10.3389/fonc.2023.1124978 google scholar
• Matsumoto N, Yoneda-Kato N, Iguchi T, et al. Elevated Mlf1 ex-pression correlates with malignant progression from myelodys-plastic syndrome. Leukemia. 2000;İ4(10):1757-1765. google scholar
• Cao L, Mitra P, Gonda TJ. The mechanism of MYB tran-scriptional regulation by MLL-AF9 oncoprotein. Sci Rep. 2019;27;9(1):20084. doi: 10.1038/s41598-019-56426-7 google scholar
• Brenne AT, Fagerli UM, Shaughnessy JD Jr, et al. High ex-pression of BCL3 in human myeloma cells is associated with increased proliferation and inferior prognosis. Eur J Haematol. 2009; 82(5):354-363. google scholar
• Davis KL. Ikaros: Master of hematopoiesis, agent of leukemia. Ther Adv Hematol. 2011;2(6):359-368. google scholar