Volume 26, Issue 1 (1-2022)                   IBJ 2022, 26(1): 36-43 | Back to browse issues page

PMID: 34773930


XML Print


Abstract:  
Background: Pattern recognition receptors, especially toll-like receptors (TLRs), as the first line of defense for pathogen detection, were found to be associated with H.­ pylori infection and gastric cancer (GC). However, the expression levels of TLRs, i.e. TLR2 and TLR4, as the main receptors sensed by H.­ pylori, still remain largely ambiguous. We aimed to investigate the patterns of key transcripts of TLR2 and TLR4 in 100 GC transcriptome data. Additionally, we evaluated TLR2 and TLR4 gene expressions in gastric biopsies of Iranian GC patients, in order to validate RNA-seq outputs. Methods: For this study, 100 runs of GC samples and controls were processed and analyzed using map read to reference. Differential gene expression method was used to distinguish between GC and normal samples in the expression of TLRs and other innate immune molecules. Also, using qRT-PCR assay, transcripts of TLRs molecules for 15 GC and 15 control samples were analyzed based on the analysis of variance and least significant differences. Results: The results clearly showed that all signaling pathways molecules of TLR4, especially TLR4 (p = 0.019), NF-κB (p ­= 0.047), IL-1β (p = 0.0096), and TNF-α (p = 0.048), were upregulated in a cancerous condition in different parts and at various stages of GC. Conclusion: Our findings suggested that molecules involved in inflammation, including TLR4 and its related pro-inflammatory cytokines, may be responsible for the development and progression of GC. Accordingly, the control of H. pylori infection reduces inflammation in the gastric system and can play an important role in preventing gastrointestinal disorders.
Type of Study: Full Length/Original Article | Subject: Cancer Biology

References
1. Carcas LP. Gastric cancer review. Journal of carcinogenesis 2014; 13: 14-14. [DOI:10.4103/1477-3163.146506]
2. Murphy KM, Weaver C. Janeway's Immunobiology. New York: W.W. Norton & Company; 2016. [DOI:10.1201/9781315533247]
3. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420(6917): 860-867. [DOI:10.1038/nature01322]
4. Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nature reviews cancer 2021; 21(6): 345-359. [DOI:10.1038/s41568-021-00347-z]
5. Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nature reviews cancer 2009; 9(1): 57-63. [DOI:10.1038/nrc2541]
6. Hobohm U, Stanford JL, Grange JM. Pathogen-associated molecular pattern in cancer immunotherapy. Critical reviews in immunology 2008; 28(2): 95-107. [DOI:10.1615/CritRevImmunol.v28.i2.10]
7. Medzhitov R. Innate Immunity and Inflammation. New York: Cold Spring Harbor Laboratory Press; 2015.
8. Hayden MS, West AP, Ghosh S. NF-κB and the immune response. Oncogene 2006; 25(51): 6758-6780. [DOI:10.1038/sj.onc.1209943]
9. Janssens S, Beyaert R. Role of Toll-like receptors in pathogen recognition. Clinical microbioogyl reviews 2003; 16(4): 637-646. [DOI:10.1128/CMR.16.4.637-646.2003]
10. Dinarello CA. Proinflammatory cytokines. Chest 2000; 118(2): 503-508. [DOI:10.1378/chest.118.2.503]
11. Pålsson-McDermott EM, O'Neill LAJ. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 2004; 113(2): 153-162. [DOI:10.1111/j.1365-2567.2004.01976.x]
12. Ito N, Tsujimoto H, Ueno H, Xie Q, Shinomiya N. Helicobacter pylori-Mediated Immunity and Signaling Transduction in Gastric Cancer. Journal of clinical medicine 2020; 9(11): 3699. [DOI:10.3390/jcm9113699]
13. Peek RM, Jr., Crabtree JE. Helicobacter infection and gastric neoplasia. The journal of pathology 2006; 208(2): 233-248. [DOI:10.1002/path.1868]
14. Lee YY, Derakhshan MH. Environmental and lifestyle risk factors of gastric cancer. Archive of iranian medicine 2013; 16(6): 358-365.
15. Fernandez-Garcia B, Eiró N, González-Reyes S, González L, Aguirre A, González LO, Del Casar JM, García-Muñiz JL, Vizoso FJ. Clinical significance of toll-like receptor 3, 4, and 9 in gastric cancer. Journal of immunotherapy 2014; 37(2): 77-83. [DOI:10.1097/CJI.0000000000000016]
16. Yuan X, Zhou Y, Wang W, Li J, Xie G, Zhao Y, Xu D, Shen L. Activation of TLR4 signaling promotes gastric cancer progression by inducing mitochondrial ROS production. Cell death and disease 2013; 4(9): e794-e794. [DOI:10.1038/cddis.2013.334]
17. Su B, Ceponis PJM, Lebel S, Huynh H, Sherman PM. Helicobacter pylori activates Toll-like receptor 4 expression in gastrointestinal epithelial cells. Infection and immunity 2003; 71(6): 3496-3502. [DOI:10.1128/IAI.71.6.3496-3502.2003]
18. Sun X, Zhang M, El-Zataari M, Owyang SY, Eaton KA, Liu M, Chang YM, Zou W, Kao JY. TLR2 mediates Helicobacter pylori-induced tolerogenic immune response in mice. PloS one 2013; 8(9): e74595. [DOI:10.1371/journal.pone.0074595]
19. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic acids research 2001; 29(9): e45. [DOI:10.1093/nar/29.9.e45]
20. Brawner KM, Morrow CD, Smith PD. Gastric microbiome and gastric cancer. Cancer journal 2014; 20(3): 211-216. [DOI:10.1097/PPO.0000000000000043]
21. Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer letter 2014; 345(2): 196-202. [DOI:10.1016/j.canlet.2013.08.016]
22. Yamaoka Y. Mechanisms of disease: Helicobacter pylori virulence factors. Nature reviews gastroenterology hepatology 2010; 7(11): 629-641. [DOI:10.1038/nrgastro.2010.154]
23. Chmiela M, Miszczyk E, Rudnicka K. Structural modifications of Helicobacter pylori lipopo-lysaccharide: an idea for how to live in peace. World journal of gastroenterology 2014; 20(29): 9882-9897. [DOI:10.3748/wjg.v20.i29.9882]
24. Bimczok D, Grams JM, Stahl RD, Waites KB, Smythies LE, Smith PD. Stromal regulation of human gastric dendritic cells restricts the Th1 response to Helicobacter pylori. Gastroenterology 2011; 141(3): 929-938. [DOI:10.1053/j.gastro.2011.06.006]
25. Castaño-Rodríguez N, Kaakoush NO, Mitchell HM. Pattern-recognition receptors and gastric cancer. Frontiers in immunology 2014; 5: 336-336. [DOI:10.3389/fimmu.2014.00336]
26. Jencks DS, Adam JD, Borum ML, Koh JM, Stephen S, Doman DB. Overview of Current Concepts in Gastric Intestinal Metaplasia and Gastric Cancer. Gastroenterology and hepatology 2018; 14(2): 92-101.
27. Li G, Wang Z, Ye J, Zhang X, Wu H, Peng J, Song W, Chen C, Cai S, He Y, Xu J. Uncontrolled inflammation induced by AEG-1 promotes gastric cancer and poor prognosis. Cancer research 2014; 74(19): 5541-5552. [DOI:10.1158/0008-5472.CAN-14-0968]
28. West AC, Tang K, Tye H, Yu L, Deng N, Najdovska M, Lin SJ, Balic JJ, Okochi-Takada E, McGuirk P, Keogh B, McCormack W, Bhathal PS, Reilly M, Oshima M, Ushijima T, Tan P, Jenkins BJ. Identification of a TLR2-regulated gene signature associated with tumor cell growth in gastric cancer. Oncogene 2017; 36(36): 5134-5144. [DOI:10.1038/onc.2017.121]
29. Li N, Xu H, Ou Y, Feng Z, Zhang Q, Zhu Q, Cai Z. LPS-induced CXCR7 expression promotes gastric Cancer proliferation and migration via the TLR4/MD-2 pathway. Diagnostic pathology 2019; 14(1): 3-3. [DOI:10.1186/s13000-019-0780-x]
30. Guo J-C, Li J, Zhou L, Yang J-Y, Zhang Z-G, Liang Z-Y, Zhou W-X, You L, Zhang T-P, Zhao Y-P. CXCL12-CXCR7 axis contributes to the invasive phenotype of pancreatic cancer. Oncotarget 2016; 7(38): 62006-62018. [DOI:10.18632/oncotarget.11330]
31. Li N, Xu H, Ou Y, Feng Z, Zhang Q, Zhu Q, Cai Z. LPS-induced CXCR7 expression promotes gastric Cancer proliferation and migration via the TLR4/MD-2 pathway. Diagnostic pathology 2019; 14(1): 3. [DOI:10.1186/s13000-019-0780-x]
32. Salazar N, Muñoz D, Kallifatidis G, Singh RK, Jordà M, Lokeshwar BL. The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation. Molecular Cancer 2014; 13: 198-198. [DOI:10.1186/1476-4598-13-198]
33. Seol MA, Park JH, Jeong JH, Lyu J, Han SY, Oh SM. Role of TOPK in lipopolysaccharide-induced breast cancer cell migration and invasion. Oncotarget 2017; 8(25): 40190-40203. [DOI:10.18632/oncotarget.15360]
34. Zhao Y, Kong X, Li X, Yan S, Yuan C, Hu W, Yang Q. Metadherin mediates lipopolysaccharide-induced migration and invasion of breast cancer cells. PloS one 2011; 6(12): e29363. [DOI:10.1371/journal.pone.0029363]

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.