Author(s):
Bogi Pratomo Wibowo, Handono Kalim, Husnul Khotimah, Hidayat Sujuti, Ettie Rukmigarsari
Email(s):
bogi.pratomo@gmail.com , hkalim333@gmail.com , husnul_farmako.fk@ub.ac.id , hidayatsujuti.fk@ub.ac.id , rukmigarsari67@gmail.com
DOI:
10.52711/0974-360X.2024.00406 
Address:
Bogi Pratomo Wibowo1*, Handono Kalim2, Husnul Khotimah3, Hidayat Sujuti4, Ettie Rukmigarsari5
1Doctoral Program in Medical Science, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia 65145.
2Rheumatology and Immunology Division, Department of Internal Medicine, Faculty of Medicine, Universitas Brawijaya and Saiful Anwar General Hospital, Malang, Indonesia 65112.
3Department of Pharmacology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia 65145.
4Department of Biochemistry/Biomolecular Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia 65145.l
5Mathematics Education Study Program, Faculty of Teacher Training and Education, University of Islam Malang, Malang, Indonesia 65144.l
*Corresponding Author
Published In:
Volume - 17,
Issue - 6,
Year - 2024
ABSTRACT:
Colorectal cancer (CRC) is the second leading cause of cancer mortality due to cancer after lung cancer. Understanding detailed pathomechanisms concerned with chronic Salmonella infection, which is known to play a crucial role in CRC tumorigenesis related to AvrA protein, can contribute to the advanced management of CRC. This study aimed to find the effect of Salmonella AvrA protein on the occurrence of CRC through the TLR4/NF-?B/ß-catenin/TGF-ß pathway by analyzing whether it is empirically consistent with the theory through path analysis from the CRC mice model. The immunohistochemistry method was used for data collection for TLR4, ß-catenin, NF-?B, TGF-ß, Ki67, and apoptotic cells. Data were analyzed by creating a path analysis. A significant direct effect was shown by the expression of TLR4 to ß-catenin (p=0.000), ß-catenin to NF-?B (p=0.000), and TGF-ß to Ki67 (p=0.000). In addition, this also occurred in the expression of NF-?B to Ki67 (p=0.000) and the apoptotic percentage (p=0.020). The indirect effect was shown by the expression of TLR4 to NF-?B through ß-catenin (R=0.724; p=0.000). In addition, the expression of ß-catenin on Ki67 through NF-?B (R=0.364; p=0.000) and ß-catenin to the apoptotic percentage through NF-?B expression (R= –0.633; p=0.042). These studies explain the effect of giving Salmonella AvrA to CRC mice model through the crosstalk involvement of TLR4, ß-catenin, NF-?B, TGF-ß, and Ki67 pathway. The direct and indirect effects show consistent evidence between the Salmonella infection in the CRC mice model and the theory. Salmonella activates the TLR4 and ß-catenin pathways, triggering NF-?B pathways crucial for immune regulation, inflammation, and cell differentiation. The increased TLR4, ß-catenin, NF-?B, and TGF-ß pathway also correlated with the tumor progressivity, indicated by increased Ki67 and decreased apoptotic percentage. In conclusion, the overexpression of all pathways above by Salmonella AvrA leads to uncontrolled cell proliferation and apoptosis inhibition, consequently promoting CRC tumorigenesis.
Cite this article:
Bogi Pratomo Wibowo, Handono Kalim, Husnul Khotimah, Hidayat Sujuti, Ettie Rukmigarsari. TLR4/NF-kB/β-Catenin/TGF-β pathways in Salmonella AvrA related-Colorectal Cancer Tumorigenesis. Research Journal of Pharmacy and Technology. 2024; 17(6):2597-4. doi: 10.52711/0974-360X.2024.00406
Cite(Electronic):
Bogi Pratomo Wibowo, Handono Kalim, Husnul Khotimah, Hidayat Sujuti, Ettie Rukmigarsari. TLR4/NF-kB/β-Catenin/TGF-β pathways in Salmonella AvrA related-Colorectal Cancer Tumorigenesis. Research Journal of Pharmacy and Technology. 2024; 17(6):2597-4. doi: 10.52711/0974-360X.2024.00406 Available on: https://www.rjptonline.org/AbstractView.aspx?PID=2024-17-6-25
REFERENCES:
1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021; 71(3): 209-249. doi:10.3322/CAAC.21660
2. Hossain MS, Karuniawati H, Jairoun AA, et al. Colorectal Cancer : A Review of Carcinogenesis, Global. Cancer. 2022; 14(1732): 1-25.
3. Joy JM, Antony RJ, Rajagopal SS. Dietary Fiber Intake and Benefit of Colorectal Cancer. Asian J Res Pharm Sci. 2019; 9(3): 209-214.
4. Sun J. Impact of bacterial infection and intestinal microbiome on colorectal cancer development. Chin Med J. (Engl). 2022; 135(4): 400-408. doi:10.1097/CM9.0000000000001979
5. Sachdeo RA, Charde MS, Chakole RD. Colorectal cancer: An overview. Asian J. Res. Pharm. Sci. 2020; 10(3):211-223.
6. Rajalekshmi M, Shreedhara CS, Lobo R, Rao PP. The review on genetics, epigenetics, risk factors and diagnosis of colon cancer. Res. J. Pharm. Technol. 2018; 11(11): 5147-5151.
7. Chumduri C, Gurumurthy RK, Zietlow R, Meyer TF. Subversion of host genome integrity by bacterial pathogens. Nat Rev Mol Cell Biol. 2016; 17(10): 659-673. doi:10.1038/nrm.2016.100
8. Gagnaire A, Nadel B, Raoult D, Neefjes J, Gorvel JP. Collateral damage: insights into bacterial mechanisms that predispose host cells to cancer. Nat Rev Microbiol. 2017; 15(2): 109-128. doi:10.1038/nrmicro.2016.171
9. Shankari B, Rambabu M, Jayanthi S. Claudin-7 Inhibitors for Colon Cancer: A Computational Approach. Res J Pharm Technol. 2018; 11(8) :3415-3418.
10. Fatimah S, Rahaju AS, Rahniayu A. Role of claudin-4 and matrix metalloproteinase-2 in tumor invasion of colorectal adenocarcinoma. Res. J. Pharm. Technol. 2021; 14(9): 4795-4800.
11. Lee YP, Huang WC, Lin TJ, et al. Toll-like receptor 4 prevents AOM/ DSS-induced colitis-associated colorectal cancer in Bacteroides fragilis gnotobiotic mice.
12. Park CH, Eun CS, Han DS. Intestinal microbiota, chronic inflammation, and colorectal cancer. Intest Res. 2018; 16(3): 338. doi:10.5217/IR.2018.16.3.338
13. Deshmukh R, Kumari S, Harwansh RK. Inflammatory bowel disease: A snapshot of current knowledge. Res J Pharm Technol. 2020; 13(2): 956-962.
14. Mahore JG, Deshpande N V, Trivedi R V, Shelar AS. Ulcerative colitis: Treatment updates. Res. J. Pharm. Technol. 2020; 13(7): 3466-3471.
15. Swathi K V. Probiotics –A human friendly bacteria. Res J Pharm Technol. 2016; 9(8): 1260-1262. doi:10.5958/0974-360X.2016.00239.0
16. Zam W, Dawod R. Overview of the Probiotics' role in Gastrointestinal disorders. Res J Pharm Technol. 2020; 13(11): 5557-5561.
17. Lopez LR, Bleich RM, Arthur JC. Microbiota Effects on Carcinogenesis: Initiation, Promotion, and Progression. https://doi.org/101146/annurev-med-080719-091604. 2021; 72: 243-261. doi:10.1146/ANNUREV-MED-080719-091604
18. Scanu T, Spaapen RM, Bakker JM, et al. Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma. Cell Host Microbe. 2015; 17(6): 763-774.
19. Mughini-Gras L, Schaapveld M, Kramers J, et al. Increased colon cancer risk after severe Salmonella infection. PLoS One. 2018; 13(1): e0189721. doi:10.1371/JOURNAL.PONE.0189721
20. Liu X, Lu R, Xia Y, Wu S, Sun J. Eukaryotic signaling pathways targeted by Salmonella effector protein AvrA in intestinal infection in vivo. BMC Microbiol. 2010; 10(1): 326. doi:10.1186/1471-2180-10-326/TABLES/7
21. Lu R, Wu S, Zhang YG, et al. Enteric bacterial protein AvrA promotes colonic tumorigenesis and activates colonic beta-catenin signaling pathway. Oncog. 2014 36. 2014; 3(6): e105-e105. doi:10.1038/oncsis.2014.20
22. Lu R, Bosland M, Xia Y, Zhang YG, Kato I, Sun J. Presence of Salmonella AvrA in colorectal tumor and its precursor lesions in mouse intestine and human specimens. Oncotarget. 2017; 8(33): 55104. doi:10.18632/ONCOTARGET.19052
23. Shibolet O, Podolsky DK. TLRs in the Gut. IV. Negative regulation of Toll-like receptors and intestinal homeostasis: Addition by subtraction. Am J Physiol - Gastrointest Liver Physiol. 2007; 292(6): 1469-1473. doi:10.1152/ajpgi.00531.2006
24. James S, Namboori PK, Pappachen LK. Glutathione Derivatives as Potential Drugs for Colorectal Cancer Resulted by APC Mutations. Res J Pharm Technol. 2019; 12(8): 3911-3914.
25. Pedhazur EJ, Kerlinger FN. Multiple Regression in Behavioral Research. Holt, Rinehart, and Winston; 1982.
26. Ulevitch RJ, Tobias PS. Recognition of gram-negative bacteria and endotoxin by the innate immune system. Curr Opin Immunol. 1999; 11(1): 19-22.
27. Beilmann-Lehtonen I, Böckelman C, Mustonen H, Koskensalo S, Hagström J, Haglund C. The prognostic role of tissue TLR2 and TLR4 in colorectal cancer. Virchows Arch. 2020; 477: 705-715.
28. Wang L, Liu Q, Sun Q, Zhang C, Chen T, Cao X. TLR4 signaling in cancer cells promotes chemoattraction of immature dendritic cells via autocrine CCL20. Biochem Biophys Res Commun. 2008; 366(3): 852-856. doi:10.1016/j.bbrc.2007.12.030
29. Lu CC, Kuo HC, Wang FS, Jou MH, Lee KC, Chuang JH. Upregulation of TLRs and IL-6 as a marker in human colorectal cancer. Int J Mol Sci. 2014; 16(1): 159-177.
30. Nadeem A, Aung KM, Ray T, et al. Suppression of β‐catenin signaling in colon carcinoma cells by a bacterial protein. Int J Cancer. 2021; 149(2): 442-459.
31. Lauscher JC, Gröne J, Dullat S, et al. Association between activation of atypical NF-κB1 p105 signaling pathway and nuclear β-catenin accumulation in colorectal carcinoma. Mol Carcinog. 2010; 49(2): 121-129. doi:10.1002/MC.20606
32. Schwitalla S, Fingerle AA, Cammareri P, et al. Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties. Cell. 2013; 152(1-2): 25-38.
33. Karin M, Cao Y, Greten FR, Li ZW. NF-κB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002 24. 2002; 2(4): 301-310. doi:10.1038/nrc780
34. Cario E. Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2. Gut. 2005; 54(8): 1182-1193.
35. Patel M, Horgan PG, McMillan DC, Edwards J. NF-κB pathways in the development and progression of colorectal cancer. Transl Res. 2018; 197: 43-56.
36. Liu S, Chen S, Zeng J. TGF-β signaling: A complex role in tumorigenesis (Review). Mol Med Rep. 2018; 17(1): 699-704. doi:10.3892/MMR.2017.7970/HTML
37. Xu J, Acharya S, Sahin O, et al. 14-3-3ζ Turns TGF-β's Function from Tumor Suppressor to Metastasis Promoter in Breast Cancer by Contextual Changes of Smad Partners from p53 to Gli2. Cancer Cell. 2015; 27(2): 177-192. doi:10.1016/j.ccell.2014.11.025
38. Sjoblom T, Jones S, Wood LD, et al. The consensus coding sequences of human breast and colorectal cancers. Science (80-). 2006; 314(5797): 268-274.
39. Sun X, Xue Z, Yasin A, et al. Colorectal cancer and adjacent normal mucosa differ in apoptotic and inflammatory protein expression. Eng Regen. 2021; 2: 279-287.
40. Luo J, Chen XQ, Li P. The role of TGF-β and its receptors in gastrointestinal cancers. Transl Oncol. 2019; 12(3): 475-484.
41. Bellam N, Pasche B. Tgf-beta signaling alterations and colon cancer. Cancer Treat Res. 2010; 155: 85-103. doi:10.1007/978-1-4419-6033-7_5/COVER
42. Wang X, Yang Y, Huycke MM. Microbiome-driven carcinogenesis in colorectal cancer: Models and mechanisms. Free Radic Biol Med. 2017; 105: 3-15. doi:10.1016/j.freeradbiomed.2016.10.504
43. García-Gil A, Lopez-Bailon LU, Ortiz-Navarrete V. Beyond the antibody: B cells as a target for bacterial infection. J Leukoc Biol. 2019; 105(5): 905-913.
44. Zhang BH, Wang C, Dong W, et al. A novel approach for monitoring TGF-β signaling in vivo in colon cancer. Carcinogenesis. 2021; 42(4): 631-639. doi:10.1093/CARCIN/BGAA142
45. De Azambuja E, Cardoso F, De Castro G, et al. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients. Br J Cancer. 2007 9610. 2007; 96(10): 1504-1513. doi:10.1038/sj.bjc.6603756
46. Li LT, Jiang G, Chen Q, Zheng JN. Predic Ki67 is a promising molecular target in the diagnosis of cancer (Review). Mol Med Rep. 2015; 11(3): 1566-1572. doi:10.3892/MMR.2014.2914/HTML