Analysis of gene expression patterns in various topographic sites of gastritis patients infected with Helicobacter pylori
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Abstract
Background and Objectives: Helicobacter pylori infection primarily contributes to gastric carcinogenesis. This study examined the expression of cyclin E1, β-catenin, PPAR-δ, and miR-9 in different gastric regions of gastritis patients with and without H. pylori infection.
Materials and Methods: Gastric biopsies were obtained from 108 participants divided into three groups, including healthy (n = 15), gastritis (n = 53), and H. pylori-positive gastritis (n = 40). Bacterial culture and molecular characterization were performed to confirm H. pylori presence. Gene expression was assessed using SYBR Green-based RT-qPCR. Statistical analyses revealed correlations between the expression of cyclin E1, β-catenin, PPAR-δ, miR-9, and the presence of H. pylori in patients with gastritis compared to healthy controls.
Results: The cagA-positive strains were significantly associated with the expression of cyclin E1, β-catenin, PPAR-δ (P < 0.001), and miR-9 (P < 0.01). Cyclin E1 and β-catenin expression were upregulated in gastritis and H. pylori-positive gastritis patients. The PPAR-δ expression was highest in H. pylori-positive gastritis patients, specifically in the antrum tissues. miR-9 showed significant downregulation in H. pylori-positive gastritis samples.
Conclusion: cagA-positive H. pylori infection was linked to distinct gene expression changes that varied by gastric region. Further studies are needed to explore the mechanisms involved.
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2. Malfertheiner P, Camargo MC, El-Omar E, Liou JM, Peek RM, Schulz C, et al. Helicobacter pylori infection. Nat Rev Dis Primers 2023; 9: 19.
3. Fakharian F, Asgari B, Nabavi-Rad A, Sadeghi A, Soleimani N, Yadegar A, et al. The interplay between Helicobacter pylori and the gut microbiota: an emerging driver influencing immune system homeostasis and gastric carcinogenesis. Front Cell Infect Microbiol 2022; 12: 953718.
4. Baj J, Forma A, Sitarz M, Portincasa P, Garruti G, Krasowska D, et al. Helicobacter pylori virulence factors—mechanisms of bacterial pathogenicity in the gastric microenvironment. Cells 2020; 10: 27.
5. Chitapanarux T, Jesadaporn P, Chitapanarux N, Lertprasertsuke N. Chronic gastritis according to age and Helicobacter pylori in Thailand: histopathological patterns. Scand J Gastroenterol 2021; 56: 228-233.
6. Ou L, Liu H, Peng C, Zou Y, Jia J, Li H, et al. Helicobacter pylori infection facilitates cell migration and potentially impacts clinical outcomes in gastric cancer. Heliyon 2024; 10(17): e37046.
7. Usui Y, Taniyama Y, Endo M, Koyanagi YN, Kasugai Y, Oze I, et al. Helicobacter pylori, homologous-recombination genes, and gastric cancer. N Engl J Med 2023; 388: 1181-1190.
8. Ito N, Tsujimoto H, Ueno H, Xie Q, Shinomiya N. Helicobacter pylori-mediated immunity and signaling transduction in gastric cancer. J Clin Med 2020; 9: 3699.
9. Liu LP, Sheng XP, Shuai TK, Zhao YX, Li B, Li YM. Helicobacter pylori promotes invasion and metastasis of gastric cancer by enhancing heparanase expression. World J Gastroenterol 2018; 24: 4565-4577.
10. Peng Y, Xu Y, Zhang X, Deng S, Yuan Y, Luo X, et al. A novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/β-catenin signaling pathway to promote gastric cancer progression. Mol Cancer 2021; 20: 158.
11. Palrasu M, Zaika E, El-Rifai W, Garcia-Buitrago M, Piazuelo MB, Wilson KT, et al. Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells. J Clin Invest 2020; 130: 2422-2434.
12. Liu Y, Wei D, Deguchi Y, Xu W, Tian R, Liu F, et al. PPARδ dysregulation of CCL20/CCR6 axis promotes gastric adenocarcinoma carcinogenesis by remodeling gastric tumor microenvironment. Gastric Cancer 2023; 26: 904-917.
13. Lima JF, Carvalho J, Pinto-Ribeiro I, Almeida C, Wengel J, Cerqueira L, et al. Targeting miR-9 in gastric cancer cells using locked nucleic acid oligonucleotides. BMC Mol Biol 2018; 19: 6.
14. Yao X, Xie L, Zeng Y. miR-9 promotes angiogenesis via targeting sphingosine-1-phosphate receptor 1. Front Cell Dev Biol 2020; 8: 755.
15. Pang W, Li Y, Guo W, Shen H. Cyclin E: a potential treatment target to reverse cancer chemoresistance by regulating the cell cycle. Am J Transl Res 2020; 12: 5170-5187.
16. Rathee M, Umar SM, Dev AJ, Kashyap A, Mathur SR, Gogia A, et al. Canonical WNT/β-catenin signaling upregulates aerobic glycolysis in diverse cancer types. Mol Biol Rep 2024; 51: 788.
17. Wang X, Zhao G, Shao S, Yao Y. Helicobacter pylori triggers inflammation and oncogenic transformation by perturbing the immune microenvironment. Biochim Biophys Acta Rev Cancer 2024; 1879: 189139.
18. Mourenza Á, Lorente-Torres B, Durante E, Llano-Verdeja J, Aparicio JF, Fernández-López A, et al. Understanding microRNAs in the context of infection to find new treatments against human bacterial pathogens. Antibiotics (Basel) 2022; 11: 356.
19. Bohr UR, Primus A, Zagoura A, Glasbrenner B, Wex T, Malfertheiner P. A group-specific PCR assay for the detection of Helicobacteraceae in human gut. Helicobacter 2002; 7: 378-383.
20. Yadegar A, Mobarez AM, Alebouyeh M, Mirzaei T, Kwok T, Zali MR. Clinical relevance of cagL gene and virulence genotypes with disease outcomes in a Helicobacter pylori-infected population from Iran. World J Microbiol Biotechnol 2014; 30: 2481-2490.
21. Silva-García O, Valdez-Alarcón JJ, Baizabal-Aguirre VM. Wnt/β-catenin signaling as a molecular target by pathogenic bacteria. Front Immunol 2019; 10: 2135.
22. Xin X, Yang S, Kowalski J, Gerritsen ME. Peroxisome proliferator-activated receptor γ ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 1999; 274: 9116-9121.
23. Mahboobi R, Fallah F, Yadegar A, Dara N, Kazemi Aghdam M, Asgari B, et al. Expression analysis of miRNA-155 level in Helicobacter pylori-related inflammation and chronic gastritis. Iran J Microbiol 2022; 14: 495-502.
24. Hatakeyama M. Structure and function of Helicobacter pylori CagA, the first-identified bacterial protein involved in human cancer. Proc Jpn Acad Ser B Phys Biol Sci 2017; 93: 196-219.
25. Suzuki N, Murata-Kamiya N, Yanagiya K, Suda W, Hattori M, Kanda H, et al. Mutual reinforcement of inflammation and carcinogenesis by the Helicobacter pylori CagA oncoprotein. Sci Rep 2015; 5: 10024.
26. Song X, Chen HX, Wang XY, Deng XY, Xi YX, He Q, et al. H. pylori-encoded CagA disrupts tight junctions and induces invasiveness of AGS gastric carcinoma cells via Cdx2-dependent targeting of Claudin-2. Cell Immunol 2013; 286: 22-30.
27. Hume S, Dianov GL, Ramadan K. A unified model for the G1/S cell cycle transition. Nucleic Acids Res 2020; 48: 12483-12501.
28. Milioli H, Alexandrou S, Lim E, Caldon CE. Cyclin E1 and cyclin E2 in ER+ breast cancer: prospects as biomarkers and therapeutic targets. Endocr Relat Cancer 2020; 27(5): R93-R112.
29. Yong X, Tang B, Li BS, Xie R, Hu CJ, Luo G, et al. Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signaling pathways. Cell Commun Signal 2015; 13: 30.
30. Dyson NJ. RB1: a prototype tumor suppressor and an enigma. Genes Dev 2016; 30: 1492-1502.
31. Shang S, Hua F, Hu ZW. The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget 2017; 8: 33972-33989.
32. Kim S, Song G, Lee T, Kim M, Kim J, Kwon H, et al. PARsylated transcription factor EB (TFEB) regulates the expression of a subset of Wnt target genes by forming a complex with β-catenin-TCF/LEF1. Cell Death Differ 2021; 28: 2555-2570.
33. Zheng L, Qi T, Yang D, Qi M, Li D, Xiang X, et al. microRNA-9 suppresses the proliferation, invasion and metastasis of gastric cancer cells through targeting cyclin D1 and Ets1. PLoS One 2013; 8(1): e55719.
34. Katoh M, Katoh M. WNT signaling and cancer stemness. Essays Biochem 2022; 66: 319-331.
35. Rice PL, Kelloff J, Sullivan H, Driggers LJ, Beard KS, Kuwada S, et al. Sulindac metabolites induce caspase- and proteasome-dependent degradation of β-catenin protein in human colon cancer cells. Mol Cancer Ther 2003; 2: 885-892.
36. Wang H, Zhao M, Shi F, Zheng S, Xiong L, Zheng L. A review of signal pathway induced by virulent protein CagA of Helicobacter pylori. Front Cell Infect Microbiol 2023; 13: 1062803.
37. Disoma C, Zhou Y, Li S, Peng J, Xia Z. Wnt/β-catenin signaling in colorectal cancer: is therapeutic targeting even possible? Biochimie 2022; 195: 39-53.
38. Weydig C, Starzinski-Powitz A, Carra G, Löwer J, Wessler S. CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. Exp Cell Res 2007; 313: 3459-3471.
39. Yong X, Tang B, Xiao YF, Xie R, Qin Y, Luo G, et al. Helicobacter pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. Cancer Lett 2016; 374: 292-303.
40. Yu H, Zeng J, Liang X, Wang W, Zhou Y, Sun Y, et al. Helicobacter pylori promotes epithelial-mesenchymal transition in gastric cancer by downregulating programmed cell death protein 4 (PDCD4). PLoS One 2014; 9(8): e105306.
41. Sidrat T, Rehman ZU, Joo MD, Lee KL, Kong IK. Wnt/β-catenin pathway-mediated PPARδ expression during embryonic development, differentiation and disease. Int J Mol Sci 2021; 22: 1854.
42. Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan DE, et al. A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med 2012; 18: 1350-1358.
43. Song S, Wang Z, Li Y, Ma L, Jin J, Scott AW, et al. PPARδ interacts with the Hippo coactivator Yap1 to promote SOX9 expression and gastric cancer progression. Mol Cancer Res 2020; 18: 390-402.
44. Zavros Y, Merchant JL. The immune microenvironment in gastric adenocarcinoma. Nat Rev Gastroenterol Hepatol 2022; 19: 451-467.
45. He J, Hu W, Ouyang Q, Zhang S, He L, Chen W, et al. Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer. Cancer Lett 2022; 542: 215764.
46. Choi E, Roland JT, Barlow BJ, O'Neal R, Rich AE, Nam KT, et al. Cell lineage distribution atlas of the human stomach reveals heterogeneous gland populations in the gastric antrum. Gut 2014; 63: 1711-1720.
47. Ying E, Yu Q, Sun T, Xue H, Zhao XR, Zheng HC. The relationship between pepsinogen C and gastric carcinogenesis: a transgene and population study. BMC Cancer 2023; 23: 520.
2. Malfertheiner P, Camargo MC, El-Omar E, Liou JM, Peek RM, Schulz C, et al. Helicobacter pylori infection. Nat Rev Dis Primers 2023; 9: 19.
3. Fakharian F, Asgari B, Nabavi-Rad A, Sadeghi A, Soleimani N, Yadegar A, et al. The interplay between Helicobacter pylori and the gut microbiota: an emerging driver influencing immune system homeostasis and gastric carcinogenesis. Front Cell Infect Microbiol 2022; 12: 953718.
4. Baj J, Forma A, Sitarz M, Portincasa P, Garruti G, Krasowska D, et al. Helicobacter pylori virulence factors—mechanisms of bacterial pathogenicity in the gastric microenvironment. Cells 2020; 10: 27.
5. Chitapanarux T, Jesadaporn P, Chitapanarux N, Lertprasertsuke N. Chronic gastritis according to age and Helicobacter pylori in Thailand: histopathological patterns. Scand J Gastroenterol 2021; 56: 228-233.
6. Ou L, Liu H, Peng C, Zou Y, Jia J, Li H, et al. Helicobacter pylori infection facilitates cell migration and potentially impacts clinical outcomes in gastric cancer. Heliyon 2024; 10(17): e37046.
7. Usui Y, Taniyama Y, Endo M, Koyanagi YN, Kasugai Y, Oze I, et al. Helicobacter pylori, homologous-recombination genes, and gastric cancer. N Engl J Med 2023; 388: 1181-1190.
8. Ito N, Tsujimoto H, Ueno H, Xie Q, Shinomiya N. Helicobacter pylori-mediated immunity and signaling transduction in gastric cancer. J Clin Med 2020; 9: 3699.
9. Liu LP, Sheng XP, Shuai TK, Zhao YX, Li B, Li YM. Helicobacter pylori promotes invasion and metastasis of gastric cancer by enhancing heparanase expression. World J Gastroenterol 2018; 24: 4565-4577.
10. Peng Y, Xu Y, Zhang X, Deng S, Yuan Y, Luo X, et al. A novel protein AXIN1-295aa encoded by circAXIN1 activates the Wnt/β-catenin signaling pathway to promote gastric cancer progression. Mol Cancer 2021; 20: 158.
11. Palrasu M, Zaika E, El-Rifai W, Garcia-Buitrago M, Piazuelo MB, Wilson KT, et al. Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells. J Clin Invest 2020; 130: 2422-2434.
12. Liu Y, Wei D, Deguchi Y, Xu W, Tian R, Liu F, et al. PPARδ dysregulation of CCL20/CCR6 axis promotes gastric adenocarcinoma carcinogenesis by remodeling gastric tumor microenvironment. Gastric Cancer 2023; 26: 904-917.
13. Lima JF, Carvalho J, Pinto-Ribeiro I, Almeida C, Wengel J, Cerqueira L, et al. Targeting miR-9 in gastric cancer cells using locked nucleic acid oligonucleotides. BMC Mol Biol 2018; 19: 6.
14. Yao X, Xie L, Zeng Y. miR-9 promotes angiogenesis via targeting sphingosine-1-phosphate receptor 1. Front Cell Dev Biol 2020; 8: 755.
15. Pang W, Li Y, Guo W, Shen H. Cyclin E: a potential treatment target to reverse cancer chemoresistance by regulating the cell cycle. Am J Transl Res 2020; 12: 5170-5187.
16. Rathee M, Umar SM, Dev AJ, Kashyap A, Mathur SR, Gogia A, et al. Canonical WNT/β-catenin signaling upregulates aerobic glycolysis in diverse cancer types. Mol Biol Rep 2024; 51: 788.
17. Wang X, Zhao G, Shao S, Yao Y. Helicobacter pylori triggers inflammation and oncogenic transformation by perturbing the immune microenvironment. Biochim Biophys Acta Rev Cancer 2024; 1879: 189139.
18. Mourenza Á, Lorente-Torres B, Durante E, Llano-Verdeja J, Aparicio JF, Fernández-López A, et al. Understanding microRNAs in the context of infection to find new treatments against human bacterial pathogens. Antibiotics (Basel) 2022; 11: 356.
19. Bohr UR, Primus A, Zagoura A, Glasbrenner B, Wex T, Malfertheiner P. A group-specific PCR assay for the detection of Helicobacteraceae in human gut. Helicobacter 2002; 7: 378-383.
20. Yadegar A, Mobarez AM, Alebouyeh M, Mirzaei T, Kwok T, Zali MR. Clinical relevance of cagL gene and virulence genotypes with disease outcomes in a Helicobacter pylori-infected population from Iran. World J Microbiol Biotechnol 2014; 30: 2481-2490.
21. Silva-García O, Valdez-Alarcón JJ, Baizabal-Aguirre VM. Wnt/β-catenin signaling as a molecular target by pathogenic bacteria. Front Immunol 2019; 10: 2135.
22. Xin X, Yang S, Kowalski J, Gerritsen ME. Peroxisome proliferator-activated receptor γ ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 1999; 274: 9116-9121.
23. Mahboobi R, Fallah F, Yadegar A, Dara N, Kazemi Aghdam M, Asgari B, et al. Expression analysis of miRNA-155 level in Helicobacter pylori-related inflammation and chronic gastritis. Iran J Microbiol 2022; 14: 495-502.
24. Hatakeyama M. Structure and function of Helicobacter pylori CagA, the first-identified bacterial protein involved in human cancer. Proc Jpn Acad Ser B Phys Biol Sci 2017; 93: 196-219.
25. Suzuki N, Murata-Kamiya N, Yanagiya K, Suda W, Hattori M, Kanda H, et al. Mutual reinforcement of inflammation and carcinogenesis by the Helicobacter pylori CagA oncoprotein. Sci Rep 2015; 5: 10024.
26. Song X, Chen HX, Wang XY, Deng XY, Xi YX, He Q, et al. H. pylori-encoded CagA disrupts tight junctions and induces invasiveness of AGS gastric carcinoma cells via Cdx2-dependent targeting of Claudin-2. Cell Immunol 2013; 286: 22-30.
27. Hume S, Dianov GL, Ramadan K. A unified model for the G1/S cell cycle transition. Nucleic Acids Res 2020; 48: 12483-12501.
28. Milioli H, Alexandrou S, Lim E, Caldon CE. Cyclin E1 and cyclin E2 in ER+ breast cancer: prospects as biomarkers and therapeutic targets. Endocr Relat Cancer 2020; 27(5): R93-R112.
29. Yong X, Tang B, Li BS, Xie R, Hu CJ, Luo G, et al. Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signaling pathways. Cell Commun Signal 2015; 13: 30.
30. Dyson NJ. RB1: a prototype tumor suppressor and an enigma. Genes Dev 2016; 30: 1492-1502.
31. Shang S, Hua F, Hu ZW. The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget 2017; 8: 33972-33989.
32. Kim S, Song G, Lee T, Kim M, Kim J, Kwon H, et al. PARsylated transcription factor EB (TFEB) regulates the expression of a subset of Wnt target genes by forming a complex with β-catenin-TCF/LEF1. Cell Death Differ 2021; 28: 2555-2570.
33. Zheng L, Qi T, Yang D, Qi M, Li D, Xiang X, et al. microRNA-9 suppresses the proliferation, invasion and metastasis of gastric cancer cells through targeting cyclin D1 and Ets1. PLoS One 2013; 8(1): e55719.
34. Katoh M, Katoh M. WNT signaling and cancer stemness. Essays Biochem 2022; 66: 319-331.
35. Rice PL, Kelloff J, Sullivan H, Driggers LJ, Beard KS, Kuwada S, et al. Sulindac metabolites induce caspase- and proteasome-dependent degradation of β-catenin protein in human colon cancer cells. Mol Cancer Ther 2003; 2: 885-892.
36. Wang H, Zhao M, Shi F, Zheng S, Xiong L, Zheng L. A review of signal pathway induced by virulent protein CagA of Helicobacter pylori. Front Cell Infect Microbiol 2023; 13: 1062803.
37. Disoma C, Zhou Y, Li S, Peng J, Xia Z. Wnt/β-catenin signaling in colorectal cancer: is therapeutic targeting even possible? Biochimie 2022; 195: 39-53.
38. Weydig C, Starzinski-Powitz A, Carra G, Löwer J, Wessler S. CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. Exp Cell Res 2007; 313: 3459-3471.
39. Yong X, Tang B, Xiao YF, Xie R, Qin Y, Luo G, et al. Helicobacter pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer. Cancer Lett 2016; 374: 292-303.
40. Yu H, Zeng J, Liang X, Wang W, Zhou Y, Sun Y, et al. Helicobacter pylori promotes epithelial-mesenchymal transition in gastric cancer by downregulating programmed cell death protein 4 (PDCD4). PLoS One 2014; 9(8): e105306.
41. Sidrat T, Rehman ZU, Joo MD, Lee KL, Kong IK. Wnt/β-catenin pathway-mediated PPARδ expression during embryonic development, differentiation and disease. Int J Mol Sci 2021; 22: 1854.
42. Ito K, Carracedo A, Weiss D, Arai F, Ala U, Avigan DE, et al. A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med 2012; 18: 1350-1358.
43. Song S, Wang Z, Li Y, Ma L, Jin J, Scott AW, et al. PPARδ interacts with the Hippo coactivator Yap1 to promote SOX9 expression and gastric cancer progression. Mol Cancer Res 2020; 18: 390-402.
44. Zavros Y, Merchant JL. The immune microenvironment in gastric adenocarcinoma. Nat Rev Gastroenterol Hepatol 2022; 19: 451-467.
45. He J, Hu W, Ouyang Q, Zhang S, He L, Chen W, et al. Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer. Cancer Lett 2022; 542: 215764.
46. Choi E, Roland JT, Barlow BJ, O'Neal R, Rich AE, Nam KT, et al. Cell lineage distribution atlas of the human stomach reveals heterogeneous gland populations in the gastric antrum. Gut 2014; 63: 1711-1720.
47. Ying E, Yu Q, Sun T, Xue H, Zhao XR, Zheng HC. The relationship between pepsinogen C and gastric carcinogenesis: a transgene and population study. BMC Cancer 2023; 23: 520.
| Files | ||
| Issue | Vol 18 No 5 (2026) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijm.v18i5.22868 | |
| Keywords | ||
| Helicobacter pylori Gastritis Stomach neoplasms Cyclin E1 β-catenin Peroxisome proliferator-activated receptor delta MicroRNAs | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Sarrafzadeh Zargar S, Anvari M, Sadeghi A, Yadegar A. Analysis of gene expression patterns in various topographic sites of gastritis patients infected with Helicobacter pylori. Iran J Microbiol. 2026;18(5):773-786.
