The asymmetrical distribution of the cellular organelles inside the cell is maintained by a group of cell polarity proteins. The maintenance of polarity is one of the vital host defense mechanisms against pathogens, and the loss of it contributes to infection facilitation and cancer progression. Studies have suggested that infection of viruses and bacteria alters cell polarity. Helicobacter pylori and Epstein-Barr virus are group I carcinogens involved in the progression of multiple clinical conditions besides gastric cancer (GC) and Burkitt's lymphoma, respectively. Moreover, the coinfection of both these pathogens contributes to a highly aggressive form of GC. H. pylori and EBV target the host cell polarity complexes for their pathogenesis. H. pylori-associated proteins like CagA, VacA OipA, and urease were shown to imbalance the cellular homeostasis by altering the cell polarity. Similarly, EBV-associated genes LMP1, LMP2A, LMP2B, EBNA3C, and EBNA1 also contribute to altered cell asymmetry. This review summarized all the possible mechanisms involved in cell polarity deformation in H. pylori and EBV-infected epithelial cells. We have also discussed deregulated molecular pathways like NF-κB, TGF-β/SMAD, and β-catenin in H. pylori, EBV, and their coinfection that further modulate PAR, SCRIB, or CRB polarity complexes in epithelial cells.

Central Forensic Science Laboratory Pune DFSS Ministry of Home Affairs Govt of India Talegaon MIDC Phase 1 Near JCB Factory Pune Maharashtra 410506 India

Department of Bioscience and Bioengineering Indian Institute of Technology Jodhpur NH 65 Nagaur Road Karwar Jodhpur District Rajasthan 342037 India

Department of Biosciences and Biomedical Engineering Indian Institute of Technology Indore Simrol Indore Madhya Pradesh 453552 India

Himalayan School of Biosciences Swami Rama Himalayan University Swami Ram Nagar Jolly Grant Dehradun Uttarakhand 248 016 India

Infection Bioengineering Group Department of Biosciences and Biomedical Engineering Indian Institute of Technology Indore Simrol Indore Madhya Pradesh 453552 India

Zobrazit více v PubMed

Aigner K, Dampier B, Descovich L, Mikula M, Sultan A et al (2007) The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 26:6979–6988. https://doi.org/10.1038/sj.onc.1210508 PubMed DOI PMC

Alzahrani S (2014) Effect of Helicobacter pylori on gastric epithelial cells. WJG 20:12767. https://doi.org/10.3748/wjg.v20.i36.12767 PubMed DOI PMC

Baj J, Korona-Głowniak I, Forma A, Maani A, Sitarz E et al (2020) Mechanisms of the epithelial–mesenchymal transition and tumor microenvironment in Helicobacter pylori-induced gastric cancer. Cells 9:1055. https://doi.org/10.3390/cells9041055 PubMed DOI PMC

Baral B, Kashyap D, Varshney N, Verma TP, Jain AK et al (2023) Helicobacter pylori isolated from gastric juice have higher pathogenic potential than biopsy isolates. Genes Dis S2352304223001162. https://doi.org/10.1016/j.gendis.2023.03.003

Barberà MJ, Puig I, Domínguez D, Grille SJ, Esteruelas SG et al (2004) Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene 23:7345–7354. https://doi.org/10.1038/sj.onc.1207990 PubMed DOI

Bianchi M, De Lucchini S, Marin O, Turner LD, Hanks KS et al (2005) Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration. Biochem J 391:359–370. https://doi.org/10.1042/BJ20050282 PubMed DOI PMC

Buckley CE, St Johnston D (2022) Apical–basal polarity and the control of epithelial form and function. Nat Rev Mol Cell Biol 23:559–577. https://doi.org/10.1038/s41580-022-00465-y PubMed DOI

Butler MT, Wallingford JB (2017) Planar cell polarity in development and disease. Nat Rev Mol Cell Biol 18:375–388. https://doi.org/10.1038/nrm.2017.11 PubMed DOI PMC

Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco JM et al (2000) The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2:76–83. https://doi.org/10.1038/35000025 PubMed DOI

Cayrol C, Flemington E (1996) G0/G1 growth arrest mediated by a region encompassing the basic leucine zipper (bZIP) domain of the Epstein-Barr Virus transactivator Zta. J Biol Chem 271:31799–31802. https://doi.org/10.1074/jbc.271.50.31799 PubMed DOI

Chen L, Deng H, Cui H, Fang J, Zuo Z et al (2018) Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9:7204–7218. https://doi.org/10.18632/oncotarget.23208

Chesnokova LS, Nishimura SL, Hutt-Fletcher LM (2009) Fusion of epithelial cells by Epstein-Barr virus proteins is triggered by binding of viral glycoproteins gHgL to integrins αvβ6 or αvβ8. Proc Natl Acad Sci USA 106:20464–20469. https://doi.org/10.1073/pnas.0907508106 PubMed DOI PMC

Colosimo PF, Liu X, Kaplan NA, Tolwinski NS (2009) GSK3β affects apical-basal polarity and cell-cell adhesion by regulating aPKC levels. Dev Dyn NA-NA. https://doi.org/10.1002/dvdy.21963 DOI

Covacci A, Rappuoli R (2000) Tyrosine-phosphorylated bacterial proteins. J Exp Med 191:587–592. https://doi.org/10.1084/jem.191.4.587 PubMed DOI PMC

Cui X, Snapper CM (2021) Epstein Barr virus: development of vaccines and immune cell therapy for EBV-associated diseases. Front Immunol 12:734471. https://doi.org/10.3389/fimmu.2021.734471

Dávila-Collado R, Jarquín-Durán O, Dong LT, Espinoza JL (2020) Epstein-Barr virus and Helicobacter pylori co-infection in non-malignant gastroduodenal disorders. Pathogens 9:104. https://doi.org/10.3390/pathogens9020104 PubMed DOI PMC

Devenport D (2014) The cell biology of planar cell polarity. J Cell Biol 207:171–179. https://doi.org/10.1083/jcb.201408039 PubMed DOI PMC

Ellenbroek SIJ, Iden S, Collard JG (2012) Cell polarity proteins and cancer. Semin Cancer Biol 22:208–215. https://doi.org/10.1016/j.semcancer.2012.02.012 PubMed DOI

Etienne-Manneville S (2008) Polarity proteins in migration and invasion. Oncogene 27:6970–6980. https://doi.org/10.1038/onc.2008.347 PubMed DOI

Facciuto F, Bugnon Valdano M, Marziali F, Massimi F, Banks L et al (2014) Human papillomavirus (HPV)-18 E6 oncoprotein interferes with the epithelial cell polarity Par3 protein. Mol Oncol 8:533–543. https://doi.org/10.1016/j.molonc.2014.01.002 PubMed DOI PMC

Fahimi F, Tohidkia MR, Fouladi M, Aghabeygi R, Samadi N et al (2017) Pleiotropic cytotoxicity of VacA toxin in host cells and its impact on immunotherapy. Bioimpacts 7:59–71. https://doi.org/10.15171/bi.2017.08

Fan H, Zhang S, Zhang Y, Liang W, Cao B et al (2020) FERMT1 promotes gastric cancer progression by activating the NF-κB pathway and predicts poor prognosis. Cancer Biol Ther 21:815–825. https://doi.org/10.1080/15384047.2020.1792218 PubMed DOI PMC

Fotheringham JA, Coalson NE, Raab-Traub N (2012) Epstein-Barr virus latent membrane rotein-2A induces ITAM/Syk- and Akt-dependent epithelial migration through αv-integrin membrane translocation. J Virol 86:10308–10320. https://doi.org/10.1128/JVI.00853-12 PubMed DOI PMC

Fruehling S, Longnecker R (1997) The immunoreceptor tyrosine-based activation motif of Epstein-Barr virus LMP2A is essential for blocking BCR-mediated signal transduction. Virology 235:241–251. https://doi.org/10.1006/viro.1997.8690 PubMed DOI

Fukayama M, Hino R, Uozaki H (2008) Epstein-Barr virus and gastric carcinoma: virus-host interactions leading to carcinoma. Cancer Sci 99:1726–1733. https://doi.org/10.1111/j.1349-7006.2008.00888.x PubMed DOI

Fukuda M, Longnecker R (2007) Epstein-Barr virus latent membrane protein 2A mediates transformation through constitutive activation of the Ras/PI3-K/Akt pathway. J Virol 81:9299–9306. https://doi.org/10.1128/JVI.00537-07 PubMed DOI PMC

Gaur N, Gandhi J, Robertson ES, Verma SC, Kaul R et al (2015) Epstein-Barr virus latent antigens EBNA3C and EBNA1 modulate epithelial to mesenchymal transition of cancer cells associated with tumor metastasis. Tumor Biol 36:3051–3060. https://doi.org/10.1007/s13277-014-2941-6 DOI

Goodwin JM, Svensson RU, Lou HJ, Winslow MM, Turk EB et al (2014) An AMPK-independent signalling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential. Mol Cell 55:436–450. https://doi.org/10.1016/j.molcel.2014.06.021 PubMed DOI PMC

Gradoville L, Kwa D, El-Guindy A, Miller G (2002) Protein kinase C-independent activation of the Epstein-Barr virus lytic cycle. J Virol 76:5612–5626. https://doi.org/10.1128/JVI.76.11.5612-5626.2002 PubMed DOI PMC

Hatakeyama M (2004) Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer 4:688–694. https://doi.org/10.1038/nrc1433 PubMed DOI

Hatakeyama M (2008) SagA of CagA in Helicobacter pylori pathogenesis. Curr Opin Microbiol 11:30–37. https://doi.org/10.1016/j.mib.2007.12.003 PubMed DOI

Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T et al (2002) SHP-2 Tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295:683–686. https://doi.org/10.1126/science.1067147 PubMed DOI

Hino R, Uozaki H, Inoue Y, Shintani Y, Ushiku T et al (2008) Survival advantage of EBV-associated gastric carcinoma: survivin up-regulation by viral latent membrane protein 2A. Cancer Res 68:1427–1435. https://doi.org/10.1158/0008-5472.CAN-07-3027 PubMed DOI

Horikawa T, Yang J, Kondo S, Yoshizaki T, Joab I et al (2007) Twist and epithelial-mesenchymal transition are induced by the EBV oncoprotein latent membrane protein 1 and are associated with metastatic nasopharyngeal carcinoma. Cancer Res 67:1970–1978. https://doi.org/10.1158/0008-5472.CAN-06-3933 PubMed DOI

Horikawa T, Yoshizaki T, Kondo S, Furukawa M, Kaizaki Y et al (2011) Epstein-Barr virus latent membrane protein 1 induces Snail and epithelial–mesenchymal transition in metastatic nasopharyngeal carcinoma. Br J Cancer 104:1160–1167. https://doi.org/10.1038/bjc.2011.38 PubMed DOI PMC

Horridge DN, Begley AA, Kim J, Aravindan N, Fan Kexin et al (2017) Outer inflammatory protein a (OipA) of Helicobacter pylori is regulated by host cell contact and mediates CagA translocation and interleukin-8 response only in the presence of a functional cag pathogenicity island type IV secretion system. Pathog Dis 75. https://doi.org/10.1093/femspd/ftx113

Hotary KB, Allen ED, Brooks PC, Datta SN, Long WM et al (2003) Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114:33–45. https://doi.org/10.1016/S0092-8674(03)00513-0 PubMed DOI

Hoy B, Löwer M, Weydig C, Carra G, Tegtmeyer N et al (2010) Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep 11:798–804. https://doi.org/10.1038/embor.2010.114 PubMed DOI PMC

Hu Y-J, Wang Y-D, Tan F-Q, Yang W-X (2013) Regulation of paracellular permeability: factors and mechanisms. Mol Biol Rep 40:6123–6142. https://doi.org/10.1007/s11033-013-2724-y PubMed DOI

Huang Y, Wang Q, Cheng D, Ting Xu W, Hua Lu N et al (2016) Adhesion and invasion of gastric mucosa epithelial cells by Helicobacter pylori. Front Cell Infect Microbiol 6. https://doi.org/10.3389/fcimb.2016.00159

Hutt-Fletcher LM (2017) The long and complicated relationship between Epstein-Barr virus and epithelial cells. J Virol 91:e01677-e1716. https://doi.org/10.1128/JVI.01677-16 PubMed DOI

Iskit S, Schlicker A, Wessels L, Peeper DS (2015) Fra-1 is a key driver of colon cancer metastasis and a Fra-1 classifier predicts disease-free survival. Oncotarget 6:43146–43161. https://doi.org/10.18632/oncotarget.6454

Iwamoto H, Czajkowsky DM, Cover TL, Szabo G, Shao Z et al (1999) VacA from Helicobacter pylori : a hexameric chloride channel. FEBS Lett 450:101–104. https://doi.org/10.1016/S0014-5793(99)00474-3 PubMed DOI

Jakhmola S, Jha HC (2021) Glial cell response to Epstein-Barr virus infection: a plausible contribution to virus-associated inflammatory reactions in the brain. Virology 559:182–195. https://doi.org/10.1016/j.virol.2021.04.005 PubMed DOI

Janz A, Oezel M, Kurzeder C, Mautner J, Pich D et al (2000) Infectious Epstein-Barr virus lacking major glycoprotein BLLF1 (gp350/220) demonstrates the existence of additional viral ligands. J Virol 74:10142–10152. https://doi.org/10.1128/JVI.74.21.10142-10152.2000 PubMed DOI PMC

Javier RT, Rice AP (2011) Emerging theme: cellular PDZ proteins as common targets of pathogenic viruses. J Virol 85:11544–11556. https://doi.org/10.1128/JVI.05410-11 PubMed DOI PMC

Jha HC, Sun Z, Upadhyay SK, Darine W, Naccache El, Singh KR et al (2016) KSHV-mediated regulation of Par3 and SNAIL contributes to B-cell proliferation. PLoS Pathog 12:e1005801. https://doi.org/10.1371/journal.ppat.1005801

Ji R, Zhu XJ, Wang ZR, Huang LQ (2020) Cortactin in epithelial–mesenchymal transition. Front Cell Dev Biol 8:585619. https://doi.org/10.3389/fcell.2020.585619

Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428. https://doi.org/10.1172/JCI39104 PubMed DOI PMC

Kanabar D, Muth A (2020) Exploring gankyrin’s role in cancer development and its potential as a therapeutic target. Future Med Chem 12:1603–1606. https://doi.org/10.4155/fmc-2020-0200 PubMed DOI

Kaneda A, Matsusaka K, Aburatani H, Fukayama M (2012) Epstein-Barr virus infection as an epigenetic driver of tumorigenesis. Cancer Res 72:3445–3450. https://doi.org/10.1158/0008-5472.CAN-11-3919 PubMed DOI

Kashyap D, Baral B, Varshney N, Singh KA, Jha HC et al (2020) Helicobacter pylori and Epstein-Barr virus coinfection stimulates the aggressiveness in gastric cancer through the regulation of gankyrin. Msphere 6(5):e00751-e821. https://doi.org/10.1128/msphere.00751-21 DOI

Kashyap D, Rele S, Bagde PH, Saini V, Chatterjee D et al (2023) Comprehensive insight into altered host cell-signalling cascades upon Helicobacter pylori and Epstein-Barr virus infections in cancer. Arch Microbiol 205:262. https://doi.org/10.1007/s00203-023-03598-6 PubMed DOI

Kaul R, Murakami M, Choudhuri T, Robertson ES (2007) Epstein-Barr virus latent nuclear antigens can induce metastasis in a nude mouse model. J Virol 81:10352–10361. https://doi.org/10.1128/JVI.00886-07 PubMed DOI PMC

Kessenbrock K, Plaks V, Werb Z (2010) matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67. https://doi.org/10.1016/j.cell.2010.03.015 PubMed DOI PMC

Kikuchi A, Yamamoto H, Sato A, Matsumoto S (2012) Wnt5a: its signalling, functions and implication in diseases: Wnt5a signalling and cellular functions. Acta Physiol 204:17–33. https://doi.org/10.1111/j.1748-1716.2011.02294.x DOI

Kim S-M, Hur DY, Hong S-W, Kim JH (2017) EBV-encoded EBNA1 regulates cell viability by modulating miR34a-NOX2-ROS signalling in gastric cancer cells. Biochem Biophys Res Commun 494:550–555. https://doi.org/10.1016/j.bbrc.2017.10.095 PubMed DOI

Klingberg TD, Pedersen MH, Cencic A, Budde BB (2005) Application of measurements of transepithelial electrical resistance of intestinal epithelial cell monolayers to evaluate probiotic activity. Appl Environ Microbiol 71:7528–7530. https://doi.org/10.1128/AEM.71.11.7528-7530.2005 PubMed DOI PMC

Krulwich TA, Sachs G, Padan E (2011) Molecular aspects of bacterial pH sensing and homeostasis. Nat Rev Microbiol 9:330–343. https://doi.org/10.1038/nrmicro2549 PubMed DOI PMC

Kudoh A, Fujita M, Kiyono T, Kuzushima K, Sugaya Y et al (2003) Reactivation of lytic replication from B cells latently infected with Epstein-Barr virus occurs with high S-phase cyclin-dependent kinase activity while inhibiting cellular DNA replication. J Virol 77:851–861. https://doi.org/10.1128/JVI.77.2.851-861.2003 PubMed DOI PMC

Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol 15:178–196. https://doi.org/10.1038/nrm3758 PubMed DOI PMC

Li N, Xie C, Lu NH (2015) Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis. Front Cell Infect microbiol 5. https://doi.org/10.3389/fcimb.2015.00077

Lieberman PM (2013) Keeping it quiet: chromatin control of gammaherpesvirus latency. Nat Rev Microbiol 11:863–875. https://doi.org/10.1038/nrmicro3135 PubMed DOI PMC

Liu H, Ren G, Wang T, Chen Y, Gong C et al (2015) Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial–mesenchymal transition. Carcinogenesis 36:459–468. https://doi.org/10.1093/carcin/bgv017 PubMed DOI PMC

Liu HP, Chen CC, Wu CC et al (2012) Epstein-Barr virus-encoded LMP1 interacts with FGD4 to activate Cdc42 and thereby promote migration of nasopharyngeal carcinoma cells. PLoS Pathog 8:e1002690. https://doi.org/10.1371/journal.ppat.1002690

Louafi F, Martinez-Nunez RT, Sanchez-Elsner T (2010) MicroRNA-155 targets SMAD2 and modulates the response of macrophages to transforming growth factor-β. J Biol Chem 285:41328–41336. https://doi.org/10.1074/jbc.M110.146852 PubMed DOI PMC

Mandal SC, Weidmann M, Albalat A, Carrick E, Morro B et al (2020) Polarized trout epithelial cells regulate transepithelial electrical resistance, gene expression, and the phosphoproteome in response to Viral infection. Front Immunol 11:1809. https://doi.org/10.3389/fimmu.2020.01809 PubMed DOI PMC

Martin E, Girardello R, Dittmar G, Ludwig A (2021) New insights into the organization and regulation of the apical polarity network in mammalian epithelial cells. FEBS J 288:7073–7095. https://doi.org/10.1111/febs.15710 PubMed DOI

Martin-Belmonte F, Mostov K (2008) Regulation of cell polarity during epithelial morphogenesis. Curr Opin Cell Biol 20:227–234. https://doi.org/10.1016/j.ceb.2008.01.001 PubMed DOI

Matsuo Y, Kido Y, Yamaoka Y (2017) Helicobacter pylori outer membrane protein-related pathogenesis. Toxins 9:101. https://doi.org/10.3390/toxins9030101 PubMed DOI PMC

Matsusaka K, Kaneda A, Nagae G, Ushiku T, Kikuchi Y et al (2011) Classification of Epstein-Barr virus–positive gastric cancers by definition of DNA methylation epigenotypes. Cancer Res 71:7187–7197. https://doi.org/10.1158/0008-5472.CAN-11-1349 PubMed DOI

McCaffrey LM, Macara IG (2011) Epithelial organization, cell polarity and tumorigenesis. Trends Cell Biol 21:727–735. https://doi.org/10.1016/j.tcb.2011.06.005 PubMed DOI

Minamitani T, Yasui T, Ma Y, Kikutani H (2015) Evasion of affinity-based selection in germinal centers by Epstein-Barr virus LMP2A. Proc Natl Acad Sci USA 112:11612–11617. https://doi.org/10.1073/pnas.1514484112 PubMed DOI PMC

Minoura-Etoh J, Gotoh K, Sato R, Ogata M, Kaku N et al (2006) Helicobacter pylori-associated oxidant monochloramine induces reactivation of Epstein-Barr virus (EBV) in gastric epithelial cells latently infected with EBV. J Med Microbiol 55:905–911. https://doi.org/10.1099/jmm.0.46580-0 PubMed DOI

Molina-Castro SE, Tiffon C, Giraud J, Boeuf H, Sifre E et al (2020) The Hippo kinase LATS2 controls Helicobacter pylori-induced epithelial-mesenchymal transition and intestinal metaplasia in gastric mucosa. Cell Mol Gastroenterol Hepatol 9:257–276. https://doi.org/10.1016/j.jcmgh.2019.10.007 PubMed DOI

Montcouquiol M (2006) Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals. J Neurosci 26:5265–5275. https://doi.org/10.1523/JNEUROSCI.4680-05.2006 PubMed DOI PMC

Morris A, Nicholson G (1987) Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH. Am J Gastroenterol 82:192–199 PubMed

Mueller D, Tegtmeyer N, Brandt S et al (2012) c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in western and East Asian Helicobacter pylori strains. J Clin Invest 122:1553–1566. https://doi.org/10.1172/JCI61143 PubMed DOI PMC

Nakamura TY, Yamamoto I, Nishitani H, Matozaki T, Suzuki T et al (1995) Detachment of cultured cells from the substratum induced by the neutrophil-derived oxidant NH2Cl: synergistic role of phosphotyrosine and intracellular Ca2+ concentration. J Cell Biol 131:509–524. https://doi.org/10.1083/jcb.131.2.509 PubMed DOI

Nanbo A, Kachi K, Yoshiyama H, Ohba Y (2016) Epstein-Barr virus exploits host endocytic machinery for cell-to-cell viral transmission rather than a virological synapse. J Gen Virol 97:2989–3006. https://doi.org/10.1099/jgv.0.000605 PubMed DOI

Nelson WJ (2009) Remodeling epithelial cell organization: transitions between front-rear and apical-basal polarity. Cold Spring Harb Perspect Biol 1:a000513–a000513. https://doi.org/10.1101/cshperspect.a000513 PubMed DOI PMC

Noto JM, Peek RM (2017) Helicobacter pylori makes a molecular incision to gain epithelial entry. Cell Host Microbe 22:434–436. https://doi.org/10.1016/j.chom.2017.09.014 PubMed DOI PMC

Ohnishi N, Yuasa H, Tanaka S, Sawa H, Miura M et al (2008) Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc Natl Acad Sci USA 105:1003–1008. https://doi.org/10.1073/pnas.0711183105 PubMed DOI PMC

Osman MA, Bloom GS, Tagoe EA (2013) Helicobacter pylori -induced alteration of epithelial cell signalling and polarity: a possible mechanism of gastric carcinoma etiology and disparity: dysregulation of IQGAP1-signal as a driver of gastric carcinoma. Cytoskeleton 70:349–359. https://doi.org/10.1002/cm.21114 PubMed DOI

Palframan SL, Kwok T, Gabriel K (2012) Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis. Front cell inf microbio 2. https://doi.org/10.3389/fcimb.2012.00092

Papini E, Satin B, Norais N, Bernard M, Telford JL et al (1998) Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin. J Clin Invest 102:813–820. https://doi.org/10.1172/JCI2764 PubMed DOI PMC

Patra P, Rani A, Sharma N, Mukherjee C, Jha HC (2023) Unraveling the connection of Epstein-Barr virus and its glycoprotein M PubMed DOI

Rani A, Jakhmola S, Karnati S, Parmar HS, Jha HC et al (2021) Potential entry receptors for human γ-herpesvirus into epithelial cells: a plausible therapeutic target for viral infections. Tumour virus res

Ricci V, Ciacci C, Zarrilli R, Sommi P, Tummuru MK et al (1996) Effect of Helicobacter pylori on gastric epithelial cell migration and proliferation in vitro: role of VacA and CagA. Infect Immun 64:2829–2833. https://doi.org/10.1128/iai.64.7.2829-2833.1996 PubMed DOI PMC

Rodriguez A, Jung EJ, Yin Q, Cayrol C, Flemington EK et al (2001) Role of c-myc regulation in Zta-mediated induction of the cyclin-dependent kinase inhibitors p21 and p27 and cell growth arrest. Virology 284:159–169. https://doi.org/10.1006/viro.2001.0923 PubMed DOI

Royer C, Lu X (2011) Epithelial cell polarity: a major gatekeeper against cancer? Cell Death Differ 18:1470–1477. https://doi.org/10.1038/cdd.2011.60 PubMed DOI PMC

Ruch TR, Engel JN (2017) Targeting the mucosal barrier: how pathogens modulate the cellular polarity network. Cold spring harb perspect biol 9:a027953. https://doi.org/10.1101/cshperspect.a027953

Rymbai M, Ramalingam V, Samarasan I, Chandran SB, Mathew G et al (2015) Frequency of Epstein - Barr virus infection as detected by messenger RNA for EBNA 1 in histologically proven gastric adenocarcinoma in patients presenting to a tertiary care center in South India. Indian J Med Microbiol 33:369–373. https://doi.org/10.4103/0255-0857.158556 PubMed DOI

Saadat I, Higashi H, Obuse C, Umeda M, Kamiya NM et al (2007) Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447:330–333. https://doi.org/10.1038/nature05765 PubMed DOI

Saju P, Murata-Kamiya N, Hayashi T, Senda Y, Nagase L et al (2016) Host SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be downregulated by Epstein-Barr virus. Nat Microbiol 1:16026. https://doi.org/10.1038/nmicrobiol.2016.26 PubMed DOI

Schmidt TP, Perna AM, Fugmann T, Bohm M, Hiss J et al (2016) Identification of E-cadherin signature motifs functioning as cleavage sites for Helicobacter pylori HtrA. Sci Rep 6:23264. https://doi.org/10.1038/srep23264 PubMed DOI PMC

Scholle F, Bendt KM, Raab-Traub N (2000) Epstein-Barr virus LMP2A transforms epithelial cells, inhibits cell differentiation, and activates Akt. J Virol 74:10681–10689. https://doi.org/10.1128/JVI.74.22.10681-10689.2000 PubMed DOI PMC

Selbach M (2003) The Helicobacter pylori CagA protein induces cortactin dephosphorylation and actin rearrangement by c-Src inactivation. EMBO J 22:515–528. https://doi.org/10.1093/emboj/cdg050 PubMed DOI PMC

Sharafutdinov I, Backert S, Tegtmeyer N (2020) Cortactin: a major cellular target of the gastric carcinogen Helicobacter pylori. Cancers 12:159. https://doi.org/10.3390/cancers12010159 PubMed DOI PMC

Shinozaki A, Sakatani T, Ushiku T, Hino R, Isogai M et al (2010) Downregulation of microRNA-200 in EBV-associated gastric carcinoma. Cancer Res 70:4719–4727. https://doi.org/10.1158/0008-5472.CAN-09-4620 PubMed DOI

Singh S, Jha HC (2017) Status of Epstein-Barr virus coinfection with Helicobacter pylori in gastric cancer. J Oncol 2017:1–17. https://doi.org/10.1155/2017/3456264 DOI

Song Y, Li Q, Liao S, Zhong K, Jin Y et al (2020) Epstein-Barr virus-encoded miR-BART11 promotes tumor-associated macrophage-induced epithelial-mesenchymal transition via targeting FOXP1 in gastric cancer. Virology 548:6–16. https://doi.org/10.1016/j.virol.2020.05.011 PubMed DOI

Sonkar C, Verma T, Chatterji D, Jain AK, Jha HC et al (2020) Status of kinases in Epstein-Barr virus and Helicobacter pylori coinfection in gastric cancer cells. BMC Cancer 20:925. https://doi.org/10.1186/s12885-020-07377-0 PubMed DOI PMC

Sonkar C, Varshney N, Koganti S, Jha HC (2022) Kinases and therapeutics in pathogen mediated gastric cancer.

Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ et al (2002) c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol 43:971–980. https://doi.org/10.1046/j.1365-2958.2002.02781.x PubMed DOI

Su W-H, Mruk DD, Wong EWP, Lui WY, Cheng CY et al (2013) Polarity protein complex Scribble/Lgl/Dlg And epithelial cell barriers. In: Cheng CY (ed) biology and regulation of blood-tissue barriers. Springer, New York, New York, NY, pp 149–170 DOI

Suzuki A, Hirata M, Kamimura K, Maniwa R, Yamanaka T et al (2004) aPKC Acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity. Curr Biol 14:1425–1435. https://doi.org/10.1016/j.cub.2004.08.021 PubMed DOI

Suzuki M, Mimuro H, Suzuki T, Park M, Yamamoto T et al (2005) Interaction of CagA with Crk plays an important role in Helicobacter pylori–induced loss of gastric epithelial cell adhesion. J Exp Med 202:1235–1247. https://doi.org/10.1084/jem.20051027 PubMed DOI PMC

Takahashi-Kanemitsu A, Knight CT, Hatakeyama M (2020) Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis. Cell Mol Immunol 17:50–63. https://doi.org/10.1038/s41423-019-0339-5 PubMed DOI

Tan S, Tompkins LS, Amieva MR (2009) Helicobacter pylori usurps cell polarity to turn the cell surface into a replicative niche. PLoS Pathog 5:e1000407. https://doi.org/10.1371/journal.ppat.1000407

Tapia R, Kralicek SE, Hecht GA (2017) Modulation of epithelial cell polarity by bacterial pathogens: EPEC modulates apical-basal polarity. Ann NY Acad Sci 1405:16–24. https://doi.org/10.1111/nyas.13388 PubMed DOI

Tegtmeyer N, Wessler S, Necchi V, Rohde M, Harrer A et al (2017) Helicobacter pylori employs a unique basolateral type iv secretion mechanism for CagA delivery. Cell Host Microbe 22:552-560.e5. https://doi.org/10.1016/j.chom.2017.09.005 PubMed DOI

Thiery JP, Acloque H, Huang RYJ, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890. https://doi.org/10.1016/j.cell.2009.11.007 PubMed DOI

Thompson MP, Kurzrock R (2004) Epstein-Barr virus and cancer. Clin Cancer Res 10:803–821. https://doi.org/10.1158/1078-0432.CCR-0670-3 PubMed DOI

Tilahun M, Gedefie A, Belayhun C, Sahle Z, Abera A et al (2022) Helicobacter pylori pathogenicity islands and giardia lamblia cysteine proteases in role of coinfection and pathogenesis. IDR 15:21–34. https://doi.org/10.2147/IDR.S346705 DOI

Tiwari D, Jakhmola S, Pathak DK, Kumar R, Jha HC et al (2020) Temporal in vitro raman spectroscopy for monitoring replication kinetics of Epstein-Barr virus infection in glial cells. ACS Omega 5:29547–29560. https://doi.org/10.1021/acsomega.0c04525 PubMed DOI PMC

Waldrip WR, Bikoff EK, Hoodless PA, Wrana JL, Robertson EJ et al (1998) Smad2 Signalling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell 92:797–808. https://doi.org/10.1016/S0092-8674(00)81407-5 PubMed DOI

Wang Y, Lu X (2015) Cell polarity: a key defence mechanism against infection and cancer cell invasion? In: Ebnet K (ed) Cell polarity 2. Springer International Publishing, Cham, pp 167–186 DOI

Wang X, Nie J, Zhou Q, Liu W, Zhu F et al (2008) Downregulation of Par-3 expression and disruption of Par complex integrity by TGF-β during the process of epithelial to mesenchymal transition in rat proximal epithelial cells. Biochim Biophys Acta Mol Basis Dis 1782:51–59. https://doi.org/10.1016/j.bbadis.2007.11.002 DOI

Whiteman EL, Liu C-J, Fearon ER, Margolis B (2008) The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes. Oncogene 27:3875–3879. https://doi.org/10.1038/onc.2008.9 PubMed DOI PMC

Woodham EF, Machesky LM (2014) Polarised cell migration: intrinsic and extrinsic drivers. Curr Opin Cell Biol 30:25–32. https://doi.org/10.1016/j.ceb.2014.05.006 PubMed DOI

Wroblewski LE, Peek RM (2011) Targeted disruption of the epithelial-barrier by Helicobacter pylori. Cell Commun Signal 9:29. https://doi.org/10.1186/1478-811X-9-29 PubMed DOI PMC

Wroblewski LE, Shen L, Ogden S, Gallo JR, Lapierre LA et al (2009) Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation. Gastroenterology 136:236–246. https://doi.org/10.1053/j.gastro.2008.10.011 PubMed DOI

Wroblewski LE, Peek RM, Wilson KT (2010) Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 23:713–739. https://doi.org/10.1128/CMR.00011-10 PubMed DOI PMC

Xie C, Jiang Y, Zhu Z, Huang S, Li W et al (2021) Actin filament debranching regulates cell polarity during cell migration and asymmetric cell division. Proc Natl Acad Sci USA 118:e2100805118. https://doi.org/10.1073/pnas.2100805118

Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939. https://doi.org/10.1016/j.cell.2004.06.006 PubMed DOI

Yang J, Liu Z, Zeng B, Hu G, Gan R et al (2020) Epstein-Barr virus-associated gastric cancer: a distinct subtype. Cancer Lett 495:191–199. https://doi.org/10.1016/j.canlet.2020.09.019 PubMed DOI

Yao Y, Wang X, Li H, Fan J, Qian X et al (2020) Phospholipase D as a key modulator of cancer progression. Biol Rev 95:911–935. https://doi.org/10.1111/brv.12592 PubMed DOI

Yong X, Tang B, Li B-S, Xie R, Hu CH et al (2015) Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signalling pathways. Cell Commun Signal 13:30. https://doi.org/10.1186/s12964-015-0111-0 PubMed DOI PMC

Zhang F, Chen C, Hu J, Su R, Zhang J et al (2019a) Molecular mechanism of Helicobacter pylori-induced autophagy in gastric cancer (review). Oncol Lett. https://doi.org/10.3892/ol.2019.10976 PubMed DOI PMC

Zhang K, Wang D, Song J (2009) Cortactin is involved in transforming growth factor-β1-induced epithelial-mesenchymal transition in AML-12 cells. ABBS 41:839–845. https://doi.org/10.1093/abbs/gmp070 PubMed DOI

Zhang K, Zhang H, Li S, Pintilie GD, Mou TC et al (2019b) Cryo-EM structures of Helicobacter pylori vacuolating cytotoxin A oligomeric assemblies at near-atomic resolution. Proc Natl Acad Sci USA 116:6800–6805. https://doi.org/10.1073/pnas.1821959116 PubMed DOI PMC