The interaction between Helicobacter pylori and autophagy: A putative mechanism involved in gastric carcinogenesis
Subject Areas : BacteriologyMarzieh Esmaeilzadeh 1 , Abbas Yadegar 2 , Farshid Kafilzadeh 3 , Mohammad Kargar 4 , Hamid Asadzadeh Aghdaei 5
1 - PhD student, Department of Microbiology, Jahrom Branch, Islamic Azad University, Jahrom, Iran.
2 - Assistant Professor, Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
3 - Professor, Department of Microbiology, Jahrom Branch, Islamic Azad University, Jahrom, Iran.
4 - Professor, Department of Microbiology, Jahrom Branch, Islamic Azad University, Jahrom, Iran.
5 - Assistant Professor, Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Keywords: Helicobacter pylori, gastric cancer, CagA, VacA, Autophagy,
Abstract :
Helicobacter pylori is a Gram-negative bacterium that colonizes the gastric tissue of more than half of the world's population and is the major risk factor for the development of gastric cancer. H. pylori is the most common bacterial pathogen in humans, and there is a significant association between H. pylori infection and gastric cancer. Autophagy is a protective process used by eukaryotic cells to maintain cell homeostasis and defend against the attack of pathogenic microbes. H. pylori can induce autophagy in epithelial cells of the stomach and professional phagocytes such as macrophages and dendritic cells. Tumor inhibitory proteins including phosphatases, PTEN, P53, and retinoblastoma protein have a positive effect on autophagy regulation. In comparison, oncogenic products such as BCL-2 and AKT/TOR pathways play an inhibitory role on autophagy. However, the relationship between regulation of autophagy and tumorigenesis is still unclear. During H. pylori infection and after the induction of autophagy, the bacterium can escape this process by downregulation of autophagy-related proteins, and/or use the autophagosome as a suitable niche for intracellular survival. In addition, autophagy can cause cell survival or cell death through the gastric cancer process. In conclusion, the role of H. pylori infection in induction or inhibition of autophagy process, and its impact on gastric carcinogenic related pathways are a matter of controversy, which need further studies to understand the interactions between the microbe and autophagy.
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_||_
References
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resistance-from biology to clinical implications. Nature Reviews Gastroenterology &
Hepatology. 2021;18:613-29.
2. Malfertheiner P, Link A, Selgrad M. Helicobacter pylori: perspectives and time trends. Nature
Reviews Gastroenterology & Hepatology. 11(10):628-638.
3. Atherton JC, Blaser MJ. Coadaptation of Helicobacter pylori and humans: ancient history,
modern implications. Journal of Clinical Investigation. 2009;119:2475-87.
4. Hatakeyama M. Helicobacter pylori and gastric carcinogenesis. Journal of Gastroenterology.
2009;44:239-48.
5. Polk DB, Peek RM, Jr. Helicobacter pylori: gastric cancer and beyond. Nature Reviews Cancer.
2010;10:403-14.
6. Petersen AM, Krogfelt KA. Helicobacter pylori: an invading microorganism? A review. FEMS
Immunology and Medical Microbiology. 2003;36:117-26.
7. Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical
Microbiology Reviews. 2006;19:449-90
8. Oleastro M, Menard A. The Role of Helicobacter pylori outer membrane proteins in adherence
and pathogenesis. Biology. 2013;2:1110-34.
9. Ricci V. Relationship between VacA to in and host cell autophagy in Helicobacter pylori
infection of the human stomach: a few answers, many questions. To ins. 2016;8:203.
10. Palframan SL, Kwok T, Gabriel K. Vacuolating cytoto in A (VacA), a key to in for
Helicobacter pylori pathogenesis. Frontiers in Cellular and Infection Microbiology.
2012;2:92.
11. Yadegar A, Mohabati Mobarez A, ali MR. Genetic diversity and amino acid sequence
polymorphism in Helicobacter pylori CagL hypervariable motif and its association with
virulence markers and gastroduodenal diseases. Cancer Medicine. 2019;8:1619-32.
12. Phuc BH, Tuan VP, Dung HDQ, Binh TT, Tung PH, Tri TD, Thuan NPM, Khien VV, Trang
TTH, Akada J, Matsumoto T, Yamaoka Y. Helicobacter pylori type 4 secretion systems as
gastroduodenal disease markers. Scientific Reports 2021;11:4584.
13. Tegtmeyer N, Wessler S, Backert S. Role of the cag-pathogenicity island encoded type IV
secretion system in Helicobacter pylori pathogenesis. The FEBS Journal. 2011;278:
1190-1202.
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characteristics of unique components of Helicobacter pylori T4SS. The FEBS Journal.
2017;284:3540-9.
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Molecular Biology. 2012;921:41-50.
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localisation of cagA positive and cagA negative Helicobacter pylori strains in the gastric
mucosa; an in situ hybridisation study. Journal of Clinical Pathology. 2004;57:822-8.
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Helicobacter pylori CagL dependent induction of gastrin e pression via a novel
v -integrin-integrin linked kinase signalling comple . Gut. 2012;61:986-96.
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Molecular Biology. 2012;921:41-50.
19. Murata-Kamiya N, Kikuchi K, Hayashi T, Higashi H, Hatakeyama M. Helicobacter pylori
e ploits host membrane phosphatidylserine for delivery, localization, and pathophysiological
action of the CagA oncoprotein. Cell Host Microbe. 2010;7:399-411.
20. Piscione P, Mazzone M, Marcantonio MCD, Muraro R, Mincione G. Eradication of
Helicobacter pylori and gastric cancer: a controversial relationship. Frontiers in
Microbiology. 2021;12:630852.
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Physical and Biological Sciences. 2017;93:196-219.
22. Higashi H, Yokoyama K, Fujii Y, Ren S, Yuasa H, Saadat I, Murata-Kamiya N, Azuma T,
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factor CagA in mammalian cells. Journal of Biological Chemistry. 2005;280:23130-7.
23. Saadat I, Higashi H, Obuse C, Umeda M, Murata-Kamiya N, Saito Y, Lu H, Ohnishi N,
Azuma T, Suzuki A, Ohno S, Hatakeyama M. Helicobacter pylori CagA targets PAR1/MARK
kinase to disrupt epithelial cell polarity. Nature. 2007;447:330-7.
24. Noto JM, Peek RM. The role of microRNAs in Helicobacter pylori pathogenesis and gastric
carcinogenesis. Frontiers in Cellular and Infection Microbiology. 2011;1:21.
25. Chen CC, Liou JM, Lee YC, Hong TC, El-Omar EM, Wu MS. The interplay between
Helicobacter pylori and gastrointestinal microbiota. Gut Microbes. 2021;13:1909459.
26. Peek RM, Jr., Crabtree JE. Helicobacter infection and gastric neoplasia. The Journal of
Pathology. 2006;208:233-48.
27. Chang AH, Parsonnet J. Role of bacteria in oncogenesis. Clinical Microbiology Reviews.
2010;23:837-57.
28. Peek RM, Jr, Fiske C, Wilson KT. Role of innate immunity in Helicobacter pylori-induced
gastric malignancy. Physiological Reviews. 2010;90:831-58.
29. Backert S, Naumann M. What a disorder: proinflammatory signaling pathways induced by
Helicobacter pylori. Trends in Microbiology. 2010;18:479-86.
30. D'Elios MM, Andersen LP. Inflammation, immunity, and vaccines for Helicobacter pylori.
Helicobacter. 2009;14:21-8.
31. Wang CW, Klionsky DJ. The molecular mechanism of autophagy. Molecular Medicine.
2003;9:65-76.
32. Klionsky DJ, Cregg JM, Dunn WA, Jr., Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani
S, Thumm M, Veenhuis M, Ohsumi Y. A unified nomenclature for yeast autophagy-related
genes. Developmental Cell. 2003;5:539-45.
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34. Rubinsztein DC, Codogno P, Levin B. Autophagy modulation as a potential therapeutic target
for diverse diseases. Nature Reviews Drug Discovery. 2012;11:709-30.
35. Tekirdag K, Cuervo AM. Chaperone-mediated autophagy and endosomal microautophagy:
joint by a chaperone. Journal of Biological Chemistry. 2018;293:5414-24.
36. Wirawan E, Vanden Berghe T, Lippens S, Agostinis P, Vandenabeele P. Autophagy: for
better or for worse. Cell Research. 2012;22:43-61.
37. Florey O, Overholtzer M. Autophagy proteins in macroendocytic engulfment. Trends in Cell
Biology. 2012;22:374-80.
38. Li C-J, Liao W-T, Wu M-Y, Chu P-Y. New insights into the role of autophagy in tumor
immune microenvironment. International Journal of Molecular Sciences. 2017;18:1566.
39. Deen NS, Huang SJ, Gong L, Kwok T, Devenish RJ. The impact of autophagic processes on
the intracellular fate of Helicobacter pylori. Autophagy. 2013;9:639-52.
40. Pyo JO, Nah J, Jung YK. Molecules and their functions in autophagy. E perimental &
Molecular Medicine. 2012;44:73-80.
41. Fougeray S, Pallet N. Mechanisms and biological functions of autophagy in diseased and
ageing kidneys. Nature Reviews Nephrology. 2014;11:34-45.
42. Castaño‐Rodríguez N, O Kaakoush N, Goh KL, Fock KM, Mitchel HM. Autophagy in
Helicobacter pylori infection and related gastric cancer. Helicobacter. 2015;20:353-69.
43. Kim KH, Lee MS. Autophagy-a key player in cellular and body metabolism. Nature Reviews
Endocrinology. 2014;10:322-37.
44. Wang YH, Wu JJ, Lei HY. The autophagic induction in Helicobacter pylori-infected
macrophage. E perimental Biology and Medicine (Maywood, N.J.). 2009;234:171-80.
45. Tsugawa H, Suzuki H. Reactive o ygen species-induced autophagic degradation of
Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host
Microbe. 2012;12:764-77.
46. Yahiro K, Satoh M. Low-density lipoprotein receptor-related protein-1 (LRP1) mediates
autophagy and apoptosis caused by Helicobacter pylori VacA. Journal of Biological
Chemistry. 2012;287:31104-15.
47. Terebiznik M, Raju D. Effect of Helicobacter pylori’s vacuolating cytoto in on the autophagy
pathway in gastric epithelial cells. Autophagy. 2009;5:370-9.
48. Greenfield LK, Jones NL. Helicobacter pylori and its role in gastric carcinogenesis. Trends in
Microbiology. 21:602-12.
49. Li N, Tang B, Jia Yp, hu P, huang Y, Fang Y, Li Q, Wang K, hang W-J, Guo G, Wang
T-J, Feng Y-J, Qiao B, Mao X-H, ou Q-M. Helicobacter pylori CagA protein negatively
regulates autophagy and promotes inflammatory response via c-Met-PI3K/Akt-mTOR
signaling pathway. Frontiers in Cellular and Infection Microbiology. 2017;7:417.
50. Iqbal J, Kucuk C, deLeeuw RJ, Srivastava G, Tam W, Geng H, Klinkebiel D, Christman JK,
Patel K, Cao K, Shen L, Dybkaer K, Tsui IFL, Ali H, Shimizu N, Au WY, Lam WL, Chan
WC. Genomic analyses reveal global functional alterations that promote tumor growth and
novel tumor suppressor genes in natural killer-cell malignancies. Leukemia. 2009;23:1139-51.
51. Chen N, Debnath J. Autophagy and tumorigenesis. FEBS Letters. 2010;584:1427-35.
52. Su , Yang , Xu Y, Chen Y, Yu Q. Apoptosis, autophagy, necroptosis, and cancer
metastasis. Molecular Cancer. 2015;14:48.
53. Kang MR, Kim MS, Oh JE, Kim YR, Song SY, Kim SS, Ahn CH, Yoo NJ, Lee SH.
Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in
gastric and colorectal cancers with microsatellite instability. The Journal of Pathology.
2009;217:702-6.
54. Levy J, Cacheu W, Bara MA, L’Hermitte A, Lepage P, Fraudeau M, Trentesau C,
Lemarchand J, Durand A, Crain AM, Marchiol C, Renault G, Dumont F, Letourneur F,
Delacre M, Schmitt A, Terris B, Perret C, Chamaillard M, Couty JP, Romagnolo B. Intestinal
inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune
response and suppresses tumour growth. Nature Cell Biology. 2015;17:1062-73.
55. Guo JY, Xia B, White E. Autophagy-mediated tumor promotion. Cell. 2013;155:1216-9.
56. Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, Chen G, Jin S, White
E. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes &
Development. 2007;21:1367-81.
57. Wen J, hao Y, Guo L. Ore in A induces autophagy in HCT-116 human colon cancer cells
through the ERK signaling pathway. International Journal of Molecular Medicine. 32-
37:126;2015
58. White E. Deconvoluting the conte t-dependent role for autophagy in cancer. Nature Reviews
Cancer. 2012;12:401-10.
59. Guanglin Qiu, Xuqi Li, Xiangming Ch , Chao Wei, Shicai He, Jing Lu, ongliang Jia, Ke
Pang, Lin Fan. SIRT1 is a regulator of autophagy: Implications in gastric cancer progression
and treatment. FEBS Letters. 2015;589:2034-42.
60. Tu SP, Quante M, Bhagat G, Takaishi S, Cui G, Yang XD, Muthuplani S, Shibata W, Fo JG,
Pritchard M, Wang TC. Interferon-γ inhibits gastric carcinogenesis by inducing epithelial cell
autophagy and T cell apoptosis. Cancer Research. 2011;71:4247-59.
61. Kim MS, Jeong EG, Ahn CH, Kim SS, Lee SH, Yoo NJ. Frameshift mutation of UVRAG, an
autophagyrelated gene, in gastric carcinomas with microsatellite instability. Human Pathology.
2008;39:1059-63.
62. Ahn CH, Jeong EG, Lee JW, Kim MS, Kim SH, Kim SS, Yoo NJ. Lee SH. E pression of
beclin-1, an autophagy-related protein, in gastric and colorectal cancers. APMIS.
2007;115:1344-9.
63. Yoshioka A et al. LC3, an autophagosome marker, is highly e pressed in gastrointestinal
cancers. International Journal of Oncology. 2008;33:461-8.
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