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IL-8 Links NF-κB and Wnt/β-Catenin Pathways in Persistent Inflammatory Response Induced by Chronic Helicobacter pylori Infection

  • MOLECULAR BIOLOGY OF THE CELL
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Abstract

Helicobacter pylori (H. pylori) infection can cause persistent inflammatory response in human gastric mucosal epithelial cells, which may result in the occurrence of cancer. However, the underlying mechanism of carcinogenesis has not been elucidated yet. Herein, we established the models of chronic H. pylori infection in GES-1 cells and C57BL/6J mice. Interleukin 8 (IL-8) level was detected by ELISA. The expression of NF-κB p65, IL-8, Wnt2 and β-catenin mRNA and proteins was evaluated by real-time PCR, Western blotting, immunofluorescence staining, and immunohistochemistry. The infection of H. pylori in mice was evaluated by rapid urease test, H&E staining and Warthin‒Starry silver staining. The morphological changes of gastric mucosa were observed by electron microscopy. Our results showed that in H. pylori infected gastric mucosal cells along with activation of NF-κB signaling pathway and increase of IL-8 level, the expression of Wnt2 was also increased significantly, which preliminarily indicates that IL-8 can positively regulate the expression of Wnt2. Studies in chronic H. pylori infected C57BL/6J mice models showed that there was an increased incidence of premalignant lesions in the gastric mucosa tissue. Through comparing changes of gastric mucosal cell ultrastructure and analyzing the relationship between NF-κB signaling pathway and Wnt2 expression, we found that H. pylori infection activated NF-κB signal pathways, and the massive release of IL-8 was positively correlated with the high expression of Wnt2 protein. Subsequently, the activated Wnt/β-catenin signal pathways may be involved in the malignant transformation of gastric mucosal cells. Collectively, H. pylori chronic infection may continuously lead to persistent inflammatory response: activate NF-κB pathway, promote IL-8 release and thereby activate Wnt/β-catenin pathway. IL-8 probably plays an important role of a linker in coupling these two signal pathways.

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REFERENCES

  1. Dvorak H.F. 1986. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650‒1659.

    Article  CAS  PubMed  Google Scholar 

  2. Medzhitov R. 2007. Recognition of microorganisms and activation of the immune response. Nature. 449, 819‒826.

    Article  CAS  PubMed  Google Scholar 

  3. Dias A., Garcia C., Majewski M., Wallner G., McCallum R.W., Poplawski C., Sarosiek J. 2011. Gastric juice prostaglandins and peptide growth factors as potential markers of chronic atrophic gastritis, intestinal metaplasia and gastric cancer: their potential clinical implications based on this pilot study. Dig. Dis. Sci. 56, 3220‒3225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hussain S.P., Harris C.C. 2007. Inflammation and cancer: an ancient link with novel potentials. Int. J. Cancer. 121, 2373‒2380.

    Article  CAS  PubMed  Google Scholar 

  5. Murata M. 2018. Inflammation and cancer. Environ. Health Prevent. Med. 23, 50.

    Article  Google Scholar 

  6. 2020. Erratum: Global cancer statistics 2018: GL-OBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 70, 313.

  7. Vogtmann E., Goedert J.J. 2016. Epidemiologic studies of the human microbiome and cancer. Br. J. Cancer. 114, 237‒242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Parsonnet J. 1994. Gastric adenocarcinoma and Helicobacter pylori infection. Western J. Med. 161, 60.

    CAS  Google Scholar 

  9. Valenzuela M.A., Canales J., Corvalan A.H., Quest A.F. 2015. Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis. W. J. Gastroenterol. 21, 12742‒12756.

    Article  CAS  Google Scholar 

  10. Clarke S.J., Chua W., Moore M., Kao S., Phan V., Tan C., Charles K., McMillan D.C. 2011. Use of inflammatory markers to guide cancer treatment. Clin. Pharmacol. Ther. 90, 475‒478.

    Article  CAS  PubMed  Google Scholar 

  11. Pflug K.M., Sitcheran R. 2020. Targeting NF-kappaB-inducing kinase (NIK) in immunity, inflammation, and cancer. Int. J. Mol. Sci. 21 (22), 8470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Taniguchi K., Karin M. 2018. NF-kappaB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 18, 309‒324.

    Article  CAS  PubMed  Google Scholar 

  13. Cartwright T., Perkins N.D., Wilson C.L. 2016. NFKB1: a suppressor of inflammation, ageing and cancer. FEBS J. 283, 1812‒1822.

    Article  CAS  PubMed  Google Scholar 

  14. Valovka T., Hottiger M.O. 2011. p65 controls NF-kappaB activity by regulating cellular localization of IκBβ. Biochem. J. 434, 253‒263.

    Article  CAS  PubMed  Google Scholar 

  15. Maeda S., Omata M. 2008. Inflammation and cancer: role of nuclear factor-kappaB activation. Cancer Sci. 99, 836‒842.

    Article  CAS  PubMed  Google Scholar 

  16. Greten F.R., Eckmann L., Greten T.F., Park J.M., Li Z.W., Egan L.J., Kagnoff M.F., Karin M. 2004. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 118, 285‒296.

    Article  CAS  PubMed  Google Scholar 

  17. Keates S., Hitti Y.S., Upton M., Kelly C.P. 1997. Helicobacter pylori infection activates NF-kappa B in gastric epithelial cells. Gastroenterology. 113, 1099‒1109.

    Article  CAS  PubMed  Google Scholar 

  18. Gambhir S., Vyas D., Hollis M., Aekka A., Vyas A. 2015. Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies. World J. Gastroenterol. 21, 3174‒3183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Palena C., Hamilton D.H., Fernando R.I. 2012. Influence of IL-8 on the epithelial-mesenchymal transition and the tumor microenvironment. Future Oncol. 8, 713‒722.

    Article  CAS  PubMed  Google Scholar 

  20. Visciano C., Liotti F., Prevete N., Cali G., Franco R., Collina F., de Paulis A., Marone G., Santoro M., Melillo R.M. 2015. Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8-Akt-Slug pathway. Oncogene. 34, 5175‒5186.

    Article  CAS  PubMed  Google Scholar 

  21. Clevers H., Nusse R. 2012. Wnt/beta-catenin signaling and disease. Cell. 149, 1192‒205.

    Article  CAS  PubMed  Google Scholar 

  22. Chiurillo M.A. 2015. Role of the Wnt/beta-catenin pathway in gastric cancer: an in-depth literature review. World J. Exp. Med. 5, 84‒102.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Katoh M. 2003. WNT2 and human gastrointestinal cancer (review). Int. J. Mol. Med. 12, 811‒816.

    CAS  PubMed  Google Scholar 

  24. Kikuchi A., Yamamoto H., Kishida S. 2007. Multiplicity of the interactions of Wnt proteins and their receptors. Cell. Signal. 19, 659‒671.

    Article  CAS  PubMed  Google Scholar 

  25. MacDonald B.T., Tamai K., He X. 2009. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell. 17, 9‒26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Katoh M. 2001. Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer. Int. J. Oncol. 19, 1003‒1007.

    CAS  PubMed  Google Scholar 

  27. Cheng X.X., Wang Z.C., Chen X., Sun Y., Kong Q.Y., Liu J., Gao X., Guan H.W., Li H. 2005. Frequent loss of membranous E-cadherin in gastric cancers: a cross-talk with Wnt in determining the fate of beta-catenin. Clin. Exp. Metastasis. 22, 85‒93.

    Article  CAS  PubMed  Google Scholar 

  28. Lin L., Wei H., Yi J., Xie B., Chen J., Zhou C., Wang L., Yang Y. 2019. Chronic CagA-positive Helicobacter pylori infection with MNNG stimulation synergistically induces mesenchymal and cancer stem cell-like properties in gastric mucosal epithelial cells. J. Cell. Biochem. 120, 17635‒17649.

    Article  CAS  PubMed  Google Scholar 

  29. Keszei A.P., Goldbohm R.A., Schouten L.J., Jakszyn P., van den Brandt P.A. 2013. Dietary N-nitroso compounds, endogenous nitrosation, and the risk of esophageal and gastric cancer subtypes in the Netherlands Cohort Study. Am. J. Clin. Nutr. 97, 135‒146.

    Article  CAS  PubMed  Google Scholar 

  30. Jakszyn P., Bingham S., Pera G., Agudo A., Luben R., Welch A., Boeing H., Del Giudice G., Palli D., Saieva C., Krogh V., Sacerdote C., Tumino R., Panico S., Berglund G., Siman H., Hallmans G., Sanchez M.J., Larranaga N., Barricarte A., Chirlaque M.D., Quiros J.R., Key T.J., Allen N., Lund E., Carneiro F., Linseisen J., Nagel G., Overvad K., Tjonneland A., Olsen A., Bueno-de-Mesquita H.B., Ocke M.O., Peeters P.H., Numans M.E., Clavel-Chapelon F., Trichopoulou A., Fenger C., Stenling R., Ferrari P., Jenab M., Norat T., Riboli E., Gonzalez C.A. 2006. Endogenous versus exogenous exposure to N-nitroso compounds and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST) study. Carcinogenesis. 27, 1497‒1501.

    Article  CAS  PubMed  Google Scholar 

  31. Ah-Koon L., Lesage D., Lemadre E., Souissi I., Fagard R., Varin-Blank N., Fabre E.E., Schischmanoff O. 2016. Cellular response to alkylating agent MNNG is impaired in STAT1-deficients cells. J. Cell. Mol. Med. 20, 1956‒1965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang C., Cai T., Zeng X., Cai D., Chen Y., Huang X., Gan H., Zhuo J., Zhao Z., Pan H., Li S. 2018. Astragaloside IV reverses MNNG-induced precancerous lesions of gastric carcinoma in rats: Regulation on glycolysis through miRNA-34a/LDHA pathway. Phytother. Res. 32, 1364‒1372.

    Article  CAS  PubMed  Google Scholar 

  33. Yan Z., Xu T.T., An Z.T., Hu Y., Chen W.Z., Zhu F.S. 2018. Injury of human gastric epithelial GES-1 cells by MNNG and its effects on Wnt/beta-catenin signaling pathway. Sheng Li Xue Bao. 70, 262‒268.

    PubMed  Google Scholar 

  34. Tsukamoto T., Mizoshita T., Tatematsu M. 2007. Animal models of stomach carcinogenesis. Toxicol. Pathol. 35, 636‒648.

    Article  CAS  PubMed  Google Scholar 

  35. Alm R.A., Trust T.J. 1999. Analysis of the genetic diversity of Helicobacter pylori: the tale of two genomes. J. Mol. Med. 77, 834‒846.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang Y., Sun H., Chen X., Li J., Zhao H., Geng L., Li B. 2016. Functional profile of gastric epithelial cells infected with Helicobacter pylori strains. Microb. Pathog. 95, 77‒81.

    Article  CAS  PubMed  Google Scholar 

  37. Wang L., Zhou Y., Peng J., Zhang Z., Jiang D.J., Li Y.J. 2008. Role of endogenous nitric oxide synthase inhibitor in gastric mucosal injury. Can. J. Physiol. Pharmacol. 86, 97‒104.

    Article  CAS  PubMed  Google Scholar 

  38. Guo X.B., Guo L., Zhi Q.M., Ji J., Jiang J.L., Zhang R.J., Zhang J.N., Zhang J., Chen X.H., Cai Q., Li J.F., Yan M., Gu Q.L., Liu B.Y., Zhu Z.G., Yu Y.Y. 2011. Helicobacter pylori induces promoter hypermethylation and downregulates gene expression of IRX1 transcription factor on human gastric mucosa. J. Gastroenterol. Hepatol. 26, 1685‒1690.

    Article  CAS  PubMed  Google Scholar 

  39. Nurmi A., Vartiainen N., Pihlaja R., Goldsteins G., Yrjanheikki J., Koistinaho J. 2004. Pyrrolidine dithiocarbamate inhibits translocation of nuclear factor ka-ppa-B in neurons and protects against brain ischaemia with a wide therapeutic time window. J. Neurochem. 91, 755‒765.

    Article  CAS  PubMed  Google Scholar 

  40. Zhang B., Xu J., Quan Z., Qian M., Liu W., Zheng W., Yin F., Du J., Zhi Y., Song N. 2018. Klotho protein protects human keratinocytes from UVB-Induced damage possibly by reducing expression and nuclear translocation of NF-kappaB. Med. Sci. Monit. 24, 8583‒8591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Fernandes J.C., Martel-Pelletier J., Pelletier J.P. 2002. The role of cytokines in osteoarthritis pathophysiology. Biorheology. 39, 237‒246.

    CAS  PubMed  Google Scholar 

  42. Monick M.M., Aksamit T.R., Geist L.J., Hunninghake G W. 1994. Dexamethasone inhibits IL-1 and TNF activity in human lung fibroblasts without affecting IL-1 or TNF receptors. Am. J. Physiol. 267, L33‒L38.

    CAS  PubMed  Google Scholar 

  43. Seidel P., Merfort I., Hughes J.M., Oliver B.G., Tamm M., Roth M. 2009. Dimethylfumarate inhibits NF-{kappa}B function at multiple levels to limit airway smooth muscle cell cytokine secretion. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L326‒L339.

  44. Liu A.Q., Xie Z., Chen X.N., Feng J., Chen J.W., Qin F.J., Ge L.Y. 2017. Fas-associated factor 1 inhibits tumor growth by suppressing Helicobacter pylori-induced activation of NF-kappaB signaling in human gastric carcinoma. Oncotarget. 8, 7999‒8009.

    Article  PubMed  Google Scholar 

  45. Shalapour S., Karin M. 2015. Immunity, inflammation, and cancer: an eternal fight between good and evil. J. Clin. Investig. 125, 3347‒3355.

    Article  PubMed  PubMed Central  Google Scholar 

  46. David J.M., Dominguez C., Hamilton D.H., Palena C. 2016. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines. 4 (3), 22.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Perugorria M.J., Olaizola P., Labiano I., Esparza-Baquer A., Marzioni M., Marin J.J.G., Bujanda L., Banales J.M. 2019. Wnt-beta-catenin signalling in liver development, health and disease. Nat. Rev. Gastroenterol. Hepatol. 16, 121‒136.

    Article  CAS  PubMed  Google Scholar 

  48. Basu S., Cheriyamundath S., Ben-Ze’ev A. 2018. Cell–cell adhesion: linking Wnt/beta-catenin signaling with partial EMT and stemness traits in tumorigenesis. F1000Res. 7, 1488.

    Article  Google Scholar 

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ADDITIONAL INFORMATION

The text was submitted by the author(s) in English.

Funding

This work was funded by National Natural Science Foundation of China (no. 81503377), Natural Science Fund Project of Gansu Province (no. 22JR5RA729) and the Higher Education Innovation Fund Project of Gansu Province (no. 2021B-021). The funders have no role in the study.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Gansu Provincial Maternity and Child-Care Hospital, 730050, Lanzhou, Gansu, China

    L. Lin

  2. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, 730000, Lanzhou, Gansu, China

    B. Xie, J. Yi, J. Chen & H. L. Wei

  3. Department of Blood Transfusion, The Second Hospital of Lanzhou University, 730000, Lanzhou, Gansu, China

    J. Shi

  4. Department of Clinical Laboratory Center, The First Hospital of Lanzhou University, 730000, Lanzhou, Gansu, China

    C. M. Zhou

  5. Basic Medical College, Gansu University of Chinese Medicine, 730000, Lanzhou, Gansu, China

    J. X. He

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Li Lin, Bei Xie, and Jie Shi contributed equally to this article.

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Correspondence to L. Lin or H. L. Wei.

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Statement on the welfare of animals. The experimental procedures were approved by Laboratory Animal Science and Technology Management Committee of Lanzou University School of Basic Medical Sciences.

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Lin, L., Xie, B., Shi, J. et al. IL-8 Links NF-κB and Wnt/β-Catenin Pathways in Persistent Inflammatory Response Induced by Chronic Helicobacter pylori Infection. Mol Biol 57, 735–746 (2023). https://doi.org/10.1134/S0026893323040118

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