Abstract
Cancer is characterized by mutagenic events that lead to disrupted cell signaling and cellular functions. It is one of the leading causes of death worldwide. Literature suggests that pathogens, mainly Helicobacter pylori and Epstein–Barr virus (EBV), have been associated with the etiology of human cancer. Notably, their co-infection may lead to gastric cancer. Pathogen-mediated DNA damage could be the first and crucial step in the carcinogenesis process that modulates numerous cellular signaling pathways. Altogether, it dysregulates the metabolic pathways linked with cell growth, apoptosis, and DNA repair. Modulation in these pathways leads to abnormal growth and proliferation. Several signaling pathways such RTK, RAS/MAPK, PI3K/Akt, NFκB, JAK/STAT, HIF1α, and Wnt/β-catenin are known to be altered in cancer. Therefore, this review focuses on the oncogenic roles of H. pylori, EBV, and its associated signaling cascades in various cancers. Scrutinizing these signaling pathways is crucial and may provide new insights and targets for preventing and treating H. pylori and EBV-associated cancers.
Graphical abstract
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adamson AL, Darr D, Holley-Guthrie E et al (2000) Epstein–Barr virus immediate-early proteins BZLF1 and BRLF1 activate the ATF2 transcription factor by increasing the levels of phosphorylated p38 and c-Jun N-terminal kinases. J Virol 74:1224–1233. https://doi.org/10.1128/JVI.74.3.1224-1233.2000
Al Moustafa A-E, Chen D, Ghabreau L, Akil N (2009) Association between human papillomavirus and Epstein–Barr virus infections in human oral carcinogenesis. Med Hypotheses 73:184–186. https://doi.org/10.1016/j.mehy.2009.02.025
Allison CC, Kufer TA, Kremmer E et al (2009) Helicobacter pylori Induces MAPK phosphorylation and AP-1 activation via a NOD1-dependent mechanism. J Immunol 183:8099–8109. https://doi.org/10.4049/jimmunol.0900664
Allison CC, Ferrand J, McLeod L et al (2013) Nucleotide oligomerization domain 1 enhances IFN-γ signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease severity. J Immunol 190:3706–3715. https://doi.org/10.4049/jimmunol.1200591
Ambrosio MR, Navari M, Di Lisio L et al (2014) The Epstein Barr-encoded BART-6-3p microRNA affects regulation of cell growth and immuno response in Burkitt lymphoma. Infect Agent Cancer 9:12. https://doi.org/10.1186/1750-9378-9-12
Andersen-Nissen E, Smith KD, Strobe KL et al (2005) Evasion of Toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci 102:9247–9252. https://doi.org/10.1073/pnas.0502040102
Anderson LJ, Longnecker R (2008) EBV LMP2A provides a surrogate pre-B cell receptor signal through constitutive activation of the ERK/MAPK pathway. J Gen Virol 89:1563–1568. https://doi.org/10.1099/vir.0.2008/001461-0
Arachchi PS, Fernando N, Weerasekera MM et al (2017) Proinflammatory cytokine IL-17 shows a significant association with Helicobacter pylori infection and disease severity. Gastroenterol Res Pract 2017:1–7. https://doi.org/10.1155/2017/6265150
Bentz GL, Shackelford J, Pagano JS (2012) Epstein–Barr virus latent membrane protein 1 regulates the function of interferon regulatory factor 7 by inducing its sumoylation. J Virol 86:12251–12261. https://doi.org/10.1128/JVI.01407-12
Berra E, Roux D, Richard DE, Pouysségur J (2001) Hypoxia-inducible factor-1α (HIF-1α) escapes O2-driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm. EMBO Rep 2:615–620. https://doi.org/10.1093/embo-reports/kve130
Boehm D, Gewurz BE, Kieff E, Cahir-McFarland E (2010) Epstein–Barr latent membrane protein 1 transformation site 2 activates NF-κB in the absence of NF-κB essential modifier residues 133–224 or 373–419. Proc Natl Acad Sci 107:18103–18108. https://doi.org/10.1073/pnas.1011752107
Boulter L, Guest RV, Kendall TJ et al (2015) WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest 125:1269–1285. https://doi.org/10.1172/JCI76452
Bousoik E, Montazeri Aliabadi H (2018) “Do we know jack” about JAK? A closer look at JAK/STAT signaling pathway. Front Oncol 8:287. https://doi.org/10.3389/fonc.2018.00287
Bouvet M, Voigt S, Tagawa T et al (2021) Multiple viral microRNAs Regulate interferon release and signaling early during infection with Epstein–Barr virus. mBio 12:e03440-20. https://doi.org/10.1128/mBio.03440-20
Brennan P, Floettmann JE, Mehl A et al (2001) Mechanism of action of a novel latent membrane protein-1 dominant negative. J Biol Chem 276:1195–1203. https://doi.org/10.1074/jbc.M005461200
Brinkmann MM, Schulz TF (2006) Regulation of intracellular signalling by the terminal membrane proteins of members of the Gammaherpesvirinae. J Gen Virol 87:1047–1074. https://doi.org/10.1099/vir.0.81598-0
Brunet A, Bonni A, Zigmond MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868. https://doi.org/10.1016/S0092-8674(00)80595-4
Canales J, Valenzuela M, Bravo J et al (2017) Helicobacter pylori induced phosphatidylinositol-3-OH kinase/mTOR activation increases hypoxia inducible factor-1α to promote loss of cyclin D1 and G0/G1 cell cycle arrest in human gastric cells. Front Cell Infect Microbiol. https://doi.org/10.3389/fcimb.2017.00092
Ceppi M, Pereira PM, Dunand-Sauthier I et al (2009) MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells. Proc Natl Acad Sci 106:2735–2740. https://doi.org/10.1073/pnas.0811073106
Chang H, Kim N, Park JH et al (2015) Helicobacter pylori might induce TGF-β1-mediated EMT by means of cagE. Helicobacter 20:438–448. https://doi.org/10.1111/hel.12220
Chen ZJ (2005) Ubiquitin signalling in the NF-κB pathway. Nat Cell Biol 7:758–765. https://doi.org/10.1038/ncb0805-758
Chen Y-C (2006) H pylori stimulates proliferation of gastric cancer cells through activating mitogen-activated protein kinase cascade. World J Gastroenterol 12:5972. https://doi.org/10.3748/wjg.v12.i37.5972
Chen J (2012) Roles of the PI3K/Akt pathway in Epstein–Barr virus-induced cancers and therapeutic implications. World J Virol 1:154. https://doi.org/10.5501/wjv.v1.i6.154
Chen S-Y, Lu J, Shih Y-C, Tsai C-H (2002) Epstein–Barr virus latent membrane protein 2A regulates c-Jun protein through extracellular signal-regulated kinase. J Virol 76:9556–9561. https://doi.org/10.1128/JVI.76.18.9556-9561.2002
Chen Y-R, Liu M-T, Chang Y-T et al (2008) Epstein–Barr virus latent membrane protein 1 represses DNA repair through the PI3K/Akt/FOXO3a pathway in human epithelial cells. J Virol 82:8124–8137. https://doi.org/10.1128/JVI.00430-08
Chen J-P, Wu M-S, Kuo S-H, Liao F (2014) IL-22 negatively regulates Helicobacter pylori-induced CCL20 expression in gastric epithelial cells. PLoS ONE 9:e97350. https://doi.org/10.1371/journal.pone.0097350
Chen Y, Fachko DN, Ivanov NS, Skalsky RL (2021) B cell receptor-responsive miR-141 enhances Epstein–Barr virus lytic cycle via FOXO3 inhibition. mSphere 6:e00093-21. https://doi.org/10.1128/mSphere.00093-21
Cheok YY, Tan GMY, Lee CYQ et al (2022) Innate immunity crosstalk with Helicobacter pylori: pattern recognition receptors and cellular responses. Int J Mol Sci 23:7561. https://doi.org/10.3390/ijms23147561
Coffer PJ, Jin J, Woodgett JR (1998) Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J 335:1–13. https://doi.org/10.1042/bj3350001
Conteduca V, Sansonno D, Lauletta G et al (2013) H. pylori infection and gastric cancer: State of the art. Int J Oncol 42:5–18. https://doi.org/10.3892/ijo.2012.1701
Cross DAE, Alessi DR, Cohen P et al (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789. https://doi.org/10.1038/378785a0
Cullen BR (2009) Viral and cellular messenger RNA targets of viral microRNAs. Nature 457:421–425. https://doi.org/10.1038/nature07757
Darekar S, Georgiou K, Yurchenko M et al (2012) Epstein–Barr virus immortalization of human B-cells leads to stabilization of hypoxia-induced factor 1 alpha, congruent with the Warburg effect. PLoS ONE 7:e42072. https://doi.org/10.1371/journal.pone.0042072
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
Dawson CW, Tramountanis G, Eliopoulos AG, Young LS (2003) Epstein–Barr Virus latent membrane protein 1 (LMP1) activates the phosphatidylinositol 3-kinase/Akt pathway to promote cell survival and induce actin filament remodeling. J Biol Chem 278:3694–3704. https://doi.org/10.1074/jbc.M209840200
del Peso L, González-Garcı́a M, Page C, et al (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278:687–689. https://doi.org/10.1126/science.278.5338.687
Delgado-Ortega M, Marc D, Dupont J et al (2013) SOCS proteins in infectious diseases of mammals. Vet Immunol Immunopathol 151:1–19. https://doi.org/10.1016/j.vetimm.2012.11.008
Demidenko ZN, Blagosklonny MV (2011) The purpose of the HIF-1/PHD feedback loop: To limit mTOR-induced HIF-1α. Cell Cycle 10:1557–1562. https://doi.org/10.4161/cc.10.10.15789
Dhand R, Hiles I, Panayotou G et al (1994) PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J 13:522–533. https://doi.org/10.1002/j.1460-2075.1994.tb06290.x
Ding S-Z, Torok AM, Smith MF, Goldberg JB (2005) Toll-like receptor 2-mediated gene expression in epithelial cells during Helicobacter pylori infection. Helicobacter 10:193–204. https://doi.org/10.1111/j.1523-5378.2005.00311.x
Ding S-Z, Olekhnovich IN, Cover TL et al (2008) Helicobacter pylori and mitogen-activated protein kinases mediate activator protein-1 (AP-1) subcomponent protein expression and DNA-binding activity in gastric epithelial cells. FEMS Immunol Med Microbiol 53:385–394. https://doi.org/10.1111/j.1574-695X.2008.00439.x
Dunne C (2014) Factors that mediate colonization of the human stomach by Helicobacter pylori. World J Gastroenterol 20:5610. https://doi.org/10.3748/wjg.v20.i19.5610
Dykstra ML, Longnecker R, Pierce SK (2001) Epstein–Barr virus coopts lipid rafts to block the signaling and antigen transport functions of the BCR. Immunity 14:57–67. https://doi.org/10.1016/S1074-7613(01)00089-9
Eliopoulos AG, Gallagher NJ, Blake SMS et al (1999) Activation of the p38 mitogen-activated protein kinase pathway by Epstein–Barr virus-encoded latent membrane protein 1 coregulates interleukin-6 and interleukin-8 production. J Biol Chem 274:16085–16096. https://doi.org/10.1074/jbc.274.23.16085
Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562. https://doi.org/10.1038/nrc2664
Ersing I, Bernhardt K, Gewurz B (2013) NF-κB and IRF7 pathway activation by Epstein–Barr virus latent membrane protein 1. Viruses 5:1587–1606. https://doi.org/10.3390/v5061587
Franco AT, Israel DA, Washington MK et al (2005) Activation of β-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci 102:10646–10651. https://doi.org/10.1073/pnas.0504927102
Frappier L (2012) Contributions of Epstein–Barr nuclear antigen 1 (EBNA1) to cell immortalization and survival. Viruses 4:1537–1547. https://doi.org/10.3390/v4091537
Gaglia MM (2021) Anti-viral and pro-inflammatory functions of Toll-like receptors during gamma-herpesvirus infections. Virol J 18:218. https://doi.org/10.1186/s12985-021-01678-x
Gao X, Wang H, Sairenji T (2004) Inhibition of Epstein–Barr virus (EBV) reactivation by short interfering RNAs targeting p38 mitogen-activated protein kinase or c-myc in EBV-positive epithelial cells. J Virol 78:11798–11806. https://doi.org/10.1128/JVI.78.21.11798-11806.2004
Gao L, Han H, Wang H et al (2019) IL-10 knockdown with siRNA enhances the efficacy of Doxorubicin chemotherapy in EBV-positive tumors by inducing lytic cycle via PI3K/p38 MAPK/NF-kB pathway. Cancer Lett 462:12–22. https://doi.org/10.1016/j.canlet.2019.07.016
Gazon H, Barbeau B, Mesnard J-M, Peloponese J-M (2018) Hijacking of the AP-1 signaling pathway during development of ATL. Front Microbiol 8:2686. https://doi.org/10.3389/fmicb.2017.02686
Geng W, Zhang H-Y (2017) Research on the mechanism of HP mediated PI3K/AKT/GSK3β pathways in gastric cancer. Eur Rev Med Pharmacol Sci 21:33–37
Geng Y, Lu X, Wu X et al (2016) MicroRNA-27b suppresses Helicobacter pylori-induced gastric tumorigenesis through negatively regulating Frizzled7. Oncol Rep 35:2441–2450. https://doi.org/10.3892/or.2016.4572
Gewurz BE, Mar JC, Padi M et al (2011) Canonical NF-κB activation is essential for Epstein–Barr virus latent membrane protein 1 TES2/CTAR2 gene regulation. J Virol 85:6764–6773. https://doi.org/10.1128/JVI.00422-11
Gewurz BE, Towfic F, Mar JC et al (2012) Genome-wide siRNA screen for mediators of NF-κB activation. Proc Natl Acad Sci 109:2467–2472. https://doi.org/10.1073/pnas.1120542109
Gires O (1999) Latent membrane protein 1of Epstein–Barr virus interacts with JAK3 and activates STAT proteins. EMBO J 18:3064–3073. https://doi.org/10.1093/emboj/18.11.3064
Green MR, Monti S, Rodig SJ et al (2010) Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116:3268–3277. https://doi.org/10.1182/blood-2010-05-282780
Guo L, Fang T, Jiang Y, Liu D (2021) IRF7 is a Prognostic biomarker and associated with immune infiltration in stomach adenocarcinoma. Int J Gen Med 14:9887–9902. https://doi.org/10.2147/IJGM.S342607
Hatakeyama M (2014) Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis. Cell Host Microbe 15:306–316. https://doi.org/10.1016/j.chom.2014.02.008
Hayakawa Y, Hirata Y, Nakagawa H et al (2011) Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer. Proc Natl Acad Sci 108:780–785. https://doi.org/10.1073/pnas.1011418108
Hayakawa Y, Hirata Y, Kinoshita H et al (2013) Differential roles of ASK1 and TAK1 in Helicobacter pylori-induced cellular responses. Infect Immun 81:4551–4560. https://doi.org/10.1128/IAI.00914-13
Hayashi Y, Tsujii M, Wang J et al (2013) CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori -related carcinogenesis. Gut 62:1536–1546. https://doi.org/10.1136/gutjnl-2011-301625
Hayden MS, Ghosh S (2012) NF-κB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26:203–234. https://doi.org/10.1101/gad.183434.111
Hinshaw DC, Shevde LA (2019) The tumor microenvironment innately modulates cancer progression. Cancer Res 79:4557–4566. https://doi.org/10.1158/0008-5472.CAN-18-3962
Hirata Y, Ohmae T, Shibata W et al (2006) MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori -infected human epithelial cells. J Immunol 176:3796–3803. https://doi.org/10.4049/jimmunol.176.6.3796
Hooi JKY, Lai WY, Ng WK et al (2017) Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology 153:420–429. https://doi.org/10.1053/j.gastro.2017.04.022
Hooykaas MJG, van Gent M, Soppe JA et al (2017) EBV MicroRNA BART16 suppresses type I IFN signaling. J Immunol 198:4062–4073. https://doi.org/10.4049/jimmunol.1501605
Huang W-T, Lin C-W (2014) EBV-encoded miR-BART20-5p and miR-BART8 inhibit the IFN-γ–STAT1 pathway associated with disease progression in nasal NK-Cell lymphoma. Am J Pathol 184:1185–1197. https://doi.org/10.1016/j.ajpath.2013.12.024
Huang Y, Wang Q, Cheng D et al (2016) Adhesion and invasion of gastric mucosa epithelial cells by Helicobacter pylori. Front Cell Infect Microbiol. https://doi.org/10.3389/fcimb.2016.00159
Humme S, Reisbach G, Feederle R et al (2003) The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc Natl Acad Sci 100:10989–10994. https://doi.org/10.1073/pnas.1832776100
Hutajulu SH, Hoebe EK, Verkuijlen SA et al (2010) Conserved mutation of Epstein–Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. Infect Agent Cancer 5:16. https://doi.org/10.1186/1750-9378-5-16
Iwakiri D, Zhou L, Samanta M et al (2009) Epstein–Barr virus (EBV)–encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3. J Exp Med 206:2091–2099. https://doi.org/10.1084/jem.20081761
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
Jang KL, Shackelford J, Seo SY, Pagano JS (2005) Up-regulation of β-catenin by a viral oncogene correlates with inhibition of the seven in absentia homolog 1 in B lymphoma cells. Proc Natl Acad Sci 102:18431–18436. https://doi.org/10.1073/pnas.0504054102
Jiang S, Zhang H-W, Lu M-H et al (2010) MicroRNA-155 functions as an OncomiR in breast cancer by targeting the Suppressor of Cytokine Signaling 1 gene. Cancer Res 70:3119–3127. https://doi.org/10.1158/0008-5472.CAN-09-4250
Jochum W, Passegué E, Wagner EF (2001) AP-1 in mouse development and tumorigenesis. Oncogene 20:2401–2412. https://doi.org/10.1038/sj.onc.1204389
Kashyap D, Baral B, Jakhmola S et al (2021) Helicobacter pylori and Epstein–Barr virus coinfection stimulates aggressiveness in gastric cancer through the regulation of gankyrin. mSphere 6:e00751-21. https://doi.org/10.1128/mSphere.00751-21
Kashyap D, Varshney N, Parmar HS, Jha HC (2022) Gankyrin: at the crossroads of cancer diagnosis, disease prognosis, and development of efficient cancer therapeutics. Adv Cancer Biol Metastasis 4:100023. https://doi.org/10.1016/j.adcanc.2021.100023
Katso R, Okkenhaug K, Ahmadi K et al (2001) Cellular function of phosphoinositide 3-kinases: implications for development, immunity, homeostasis, and cancer. Annu Rev Cell Dev Biol 17:615–675. https://doi.org/10.1146/annurev.cellbio.17.1.615
Kim H, Iizasa H, Kanehiro Y et al (2017) Herpesviral microRNAs in cellular metabolism and immune responses. Front Microbiol 8:1318. https://doi.org/10.3389/fmicb.2017.01318
Kirikoshi H, Sekihara H, Katoh M (2001) Up-regulation of WNT10A by tumor necrosis factor α and Helicobacter pylori in gastric cancer. Int J Oncol. https://doi.org/10.3892/ijo.19.3.533
Kondo S, Wakisaka N, Schell MJ et al (2005) Epstein–Barr virus latent membrane protein 1 induces the matrix metalloproteinase-1 promoter via an Ets binding site formed by a single nucleotide polymorphism: enhanced susceptibility to nasopharyngeal carcinoma. Int J Cancer 115:368–376. https://doi.org/10.1002/ijc.20849
Kondo S, Seo SY, Yoshizaki T et al (2006) EBV latent membrane protein 1 up-regulates hypoxia-inducible factor 1α through Siah1-mediated down-regulation of prolyl hydroxylases 1 and 3 in nasopharyngeal epithelial cells. Cancer Res 66:9870–9877. https://doi.org/10.1158/0008-5472.CAN-06-1679
Kong H, You N, Chen H et al (2020) Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contributes to gastritis. Cell Death Dis 11:189. https://doi.org/10.1038/s41419-020-2391-6
Kosowicz JG, Lee J, Peiffer B et al (2017) Drug modulators of B Cell signaling pathways and Epstein–Barr virus lytic activation. J Virol 91:e00747-e817. https://doi.org/10.1128/JVI.00747-17
Kraus RJ, Yu X, Cordes BA et al (2017) Hypoxia-inducible factor-1α plays roles in Epstein–Barr virus’s natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter. PLOS Pathog 13:e1006404. https://doi.org/10.1371/journal.ppat.1006404
Kraus RJ, Cordes BA, Sathiamoorthi S et al (2020) Reactivation of Epstein–Barr virus by HIF-1α requires p53. J Virol 94:e00722-e820. https://doi.org/10.1128/JVI.00722-20
Kung C-P, Raab-Traub N (2008) Epstein–Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor through effects on Bcl-3 and STAT3. J Virol 82:5486–5493. https://doi.org/10.1128/JVI.00125-08
Kuroda T, Kitadai Y, Tanaka S et al (2005) Monocyte chemoattractant protein-1 transfection induces angiogenesis and tumorigenesis of gastric carcinoma in nude mice via macrophage recruitment. Clin Cancer Res 11:7629–7636. https://doi.org/10.1158/1078-0432.CCR-05-0798
Lamb A, Chen L-F (2010) The many roads traveled by Helicobacter pylori to NF-κB activation. Gut Microbes 1:109–113. https://doi.org/10.4161/gmic.1.2.11587
Lamb A, Chen L-F (2013) Role of the Helicobacter pylori -induced inflammatory response in the development of gastric cancer. J Cell Biochem 114:491–497. https://doi.org/10.1002/jcb.24389
Lambert SL, Martinez OM (2007) Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. J Immunol 179:8225–8234. https://doi.org/10.4049/jimmunol.179.12.8225
Laughner E, Taghavi P, Chiles K et al (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995–4004. https://doi.org/10.1128/MCB.21.12.3995-4004.2001
Lee J-W, Liu P-F, Hsu L-P et al (2009) EBV LMP-1 negatively regulates expression and pro-apoptotic activity of Par-4 in nasopharyngeal carcinoma cells. Cancer Lett 279:193–201. https://doi.org/10.1016/j.canlet.2009.01.037
Li N, Xie C, Lu N-H (2015) Transforming growth factor-β: an important mediator in Helicobacter pylori-associated pathogenesis. Front Cell Infect Microbiol. https://doi.org/10.3389/fcimb.2015.00077
Li N, Tang B, Jia Y et al (2017) Helicobacter pylori CagA protein negatively regulates autophagy and promotes inflammatory response via c-Met-PI3K/Akt-mTOR signaling pathway. Front Cell Infect Microbiol 7:417. https://doi.org/10.3389/fcimb.2017.00417
Lin X, Liu S, Luo X et al (2009) EBV-encoded LMP1 regulates Op18/stathmin signaling pathway by cdc2 mediation in nasopharyngeal carcinoma cells. Int J Cancer 124:1020–1027. https://doi.org/10.1002/ijc.23767
Lin K-M, Lin S-J, Lin J-H et al (2020) Dysregulation of dual-specificity phosphatases by Epstein–Barr virus LMP1 and Its impact on lymphoblastoid cell line survival. J Virol 94:e01837-e1919. https://doi.org/10.1128/JVI.01837-19
Liu X, Cohen JI (2016) Epstein–Barr virus (EBV) tegument protein BGLF2 promotes EBV reactivation through activation of the p38 mitogen-activated protein kinase. J Virol 90:1129–1138. https://doi.org/10.1128/JVI.01410-15
Liu Z, Hsu H, Goeddel DV, Karin M (1996) Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-κB activation prevents cell death. Cell 87:565–576. https://doi.org/10.1016/S0092-8674(00)81375-6
Liu Z, Xiao B, Tang B et al (2010) Up-regulated microRNA-146a negatively modulate Helicobacter pylori-induced inflammatory response in human gastric epithelial cells. Microbes Infect 12:854–863. https://doi.org/10.1016/j.micinf.2010.06.002
Liu X, Ji Q, Zhang C et al (2017) miR-30a acts as a tumor suppressor by double-targeting COX-2 and BCL9 in H. pylori gastric cancer models. Sci Rep 7:7113. https://doi.org/10.1038/s41598-017-07193-w
Lo AK-F, Dawson CW, Lung HL et al (2020) The therapeutic potential of targeting BARF1 in EBV-associated malignancies. Cancers 12:1940. https://doi.org/10.3390/cancers12071940
Lu F, Weidmer A, Liu C-G et al (2008) Epstein–Barr virus-induced miR-155 attenuates NF-κB signaling and stabilizes latent virus persistence. J Virol 82:10436–10443. https://doi.org/10.1128/JVI.00752-08
Lu Y, Qin Z, Wang J et al (2017) Epstein–Barr virus miR-BART6-3p inhibits the RIG-I pathway. J Innate Immun 9:574–586. https://doi.org/10.1159/000479749
Lu Y, Xiao F, Wang Y et al (2022) Prevalence of Helicobacter pylori in non-cardia gastric cancer in China: a systematic review and meta-analysis. Front Oncol 12:850389. https://doi.org/10.3389/fonc.2022.850389
Luftig M, Prinarakis E, Yasui T et al (2003) Epstein–Barr virus latent membrane protein 1 activation of NF-κB through IRAK1 and TRAF6. Proc Natl Acad Sci 100:15595–15600. https://doi.org/10.1073/pnas.2136756100
Luo Y, Liu Y, Wang C, Gan R (2021) Signaling pathways of EBV-induced oncogenesis. Cancer Cell Int 21:93. https://doi.org/10.1186/s12935-021-01793-3
Lyu X, Fang W, Cai L et al (2014) TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness. Mol Cancer 13:51. https://doi.org/10.1186/1476-4598-13-51
Ma Y, Walsh MJ, Bernhardt K et al (2017) CRISPR/Cas9 screens reveal Epstein–Barr virus-transformed B cell host dependency factors. Cell Host Microbe 21:580-591.e7. https://doi.org/10.1016/j.chom.2017.04.005
MacDonald BT, Tamai K, He X (2009) Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev Cell 17:9–26. https://doi.org/10.1016/j.devcel.2009.06.016
Maeda S, Akanuma M, Mitsuno Y et al (2001) Distinct mechanism of Helicobacter pylori-mediated NF-κB activation between gastric cancer cells and monocytic cells. J Biol Chem 276:44856–44864. https://doi.org/10.1074/jbc.M105381200
Mancao C, Hammerschmidt W (2007) Epstein–Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110:3715–3721. https://doi.org/10.1182/blood-2007-05-090142
Matusali G, Arena G, De Leo A et al (2009) Inhibition of p38 MAP kinase pathway induces apoptosis and prevents Epstein Barr virus reactivation in Raji cells exposed to lytic cycle inducing compounds. Mol Cancer 8:18. https://doi.org/10.1186/1476-4598-8-18
Mechta-Grigoriou F, Gerald D, Yaniv M (2001) The mammalian Jun proteins: redundancy and specificity. Oncogene 20:2378–2389. https://doi.org/10.1038/sj.onc.1204381
Menheniott TR, Judd LM, Giraud AS (2015) STAT3: a critical component in the response to Helicobacter pylori infection: STAT3 in Helicobacter pylori infection. Cell Microbiol 17:1570–1582. https://doi.org/10.1111/cmi.12518
Michaud F, Coulombe F, Gaudreault E et al (2010) Epstein–Barr virus interferes with the amplification of IFNα secretion by activating suppressor of cytokine signaling 3 in primary human monocytes. PLoS ONE 5:e11908. https://doi.org/10.1371/journal.pone.0011908
Minaga K, Watanabe T, Kamata K et al (2018) Nucleotide-binding oligomerization domain 1 and Helicobacter pylori infection: a review. World J Gastroenterol 24:1725–1733. https://doi.org/10.3748/wjg.v24.i16.1725
Mochida Y, Takeda K, Saitoh M et al (2000) ASK1 inhibits interleukin-1-induced NF-κB activity through disruption of TRAF6-TAK1 interaction. J Biol Chem 275:32747–32752. https://doi.org/10.1074/jbc.M003042200
Moon JW, Kong S-K, Kim BS et al (2017) IFNγ induces PD-L1 overexpression by JAK2/STAT1/IRF-1 signaling in EBV-positive gastric carcinoma. Sci Rep 7:17810. https://doi.org/10.1038/s41598-017-18132-0
Morris MA, Dawson CW, Laverick L et al (2016) The Epstein–Barr virus encoded LMP1 oncoprotein modulates cell adhesion via regulation of activin A/TGFβ and β1 integrin signalling. Sci Rep 6:19533. https://doi.org/10.1038/srep19533
Mosialos G (2001) Cytokine signaling and Epstein–Barr virus-mediated cell transformation. Cytokine Growth Factor Rev 12:259–270. https://doi.org/10.1016/S1359-6101(00)00035-6
Mrozek-Gorska P, Buschle A, Pich D et al (2019) Epstein–Barr virus reprograms human B lymphocytes immediately in the prelatent phase of infection. Proc Natl Acad Sci 116:16046–16055. https://doi.org/10.1073/pnas.1901314116
Mulherkar TH, Gómez DJ, Sandel G, Jain P (2022) Co-infection and cancer: host–pathogen interaction between dendritic cells and HIV-1, HTLV-1, and other oncogenic viruses. Viruses 14:2037. https://doi.org/10.3390/v14092037
Nagy TA, Frey MR, Yan F et al (2009) Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling. J Infect Dis 199:641–651. https://doi.org/10.1086/596660
Najjar I, Baran-Marszak F, Le Clorennec C et al (2005) Latent membrane protein 1 regulates STAT1 through NF-κB-dependent interferon secretion in Epstein–Barr virus-immortalized B cells. J Virol 79:4936–4943. https://doi.org/10.1128/JVI.79.8.4936-4943.2005
Nakayama M, Hisatsune J, Yamasaki E et al (2009) Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. J Biol Chem 284:1612–1619. https://doi.org/10.1074/jbc.M806981200
Nanbo A, Ohashi M, Yoshiyama H, Ohba Y (2018) The role of transforming growth factor β in cell-to-cell contact-mediated Epstein–Barr virus transmission. Front Microbiol 9:984. https://doi.org/10.3389/fmicb.2018.00984
Naumann M, Wessler S, Bartsch C et al (1999) Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the cag pathogenicity island. J Biol Chem 274:31655–31662. https://doi.org/10.1074/jbc.274.44.31655
Niemann CU, Wiestner A (2013) B-cell receptor signaling as a driver of lymphoma development and evolution. Semin Cancer Biol 23:410–421. https://doi.org/10.1016/j.semcancer.2013.09.001
Ning S, Pagano JS, Barber GN (2011) IRF7: activation, regulation, modification and function. Genes Immun 12:399–414. https://doi.org/10.1038/gene.2011.21
Nishioka H, Baesso I, Semenzato G et al (2003) The neutrophil-activating protein of Helicobacter pylori (HP-NAP) activates the MAPK pathway in human neutrophils. Eur J Immunol 33:840–849. https://doi.org/10.1002/eji.200323726
Noto JM, Piazuelo MB, Chaturvedi R et al (2013) Strain-specific suppression of microRNA-320 by carcinogenic Helicobacter pylori promotes expression of the antiapoptotic protein Mcl-1. Am J Physiol Gastrointest Liver Physiol 305:G786–G796. https://doi.org/10.1152/ajpgi.00279.2013
Oshima H, Hioki K, Popivanova BK et al (2011) Prostaglandin E2 signaling and bacterial infection recruit tumor-promoting macrophages to mouse gastric tumors. Gastroenterology 140:596-607.e7. https://doi.org/10.1053/j.gastro.2010.11.007
Pachathundikandi SK, Tegtmeyer N, Backert S (2013) Signal transduction of Helicobacter pylori during interaction with host cell protein receptors of epithelial and immune cells. Gut Microbes 4:454–474. https://doi.org/10.4161/gmic.27001
Pai SG, Carneiro BA, Mota JM et al (2017) Wnt/beta-catenin pathway: modulating anticancer immune response. J Hematol Oncol 10:101. https://doi.org/10.1186/s13045-017-0471-6
Payne DM, Rossomando AJ, Martino P et al (1991) Identification of the regulatory phosphorylation sites in pp42/mitogen-activated protein kinase (MAP kinase). EMBO J 10:885–892. https://doi.org/10.1002/j.1460-2075.1991.tb08021.x
Peek RM, Crabtree JE (2006) Helicobacter infection and gastric neoplasia. J Pathol 208:233–248. https://doi.org/10.1002/path.1868
Pei Y, Banerjee S, Sun Z et al (2016) EBV nuclear antigen 3C mediates regulation of E2F6 to inhibit E2F1 transcription and promote cell proliferation. PLOS Pathog 12:e1005844. https://doi.org/10.1371/journal.ppat.1005844
Pei Y, Wong JH, Jha HC et al (2020a) Epstein–Barr virus facilitates expression of KLF14 by regulating the cooperative binding of the E2F-Rb-HDAC complex in latent infection. J Virol 94:e01209-e1220. https://doi.org/10.1128/JVI.01209-20
Pei Y, Hwang N, Lang F et al (2020b) Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies target the PI3Kγ isoform. Commun Biol 3:267. https://doi.org/10.1038/s42003-020-0996-z
Petrocca F, Visone R, Onelli MR et al (2008a) E2F1-Regulated MicroRNAs impair TGFβ-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13:272–286. https://doi.org/10.1016/j.ccr.2008.02.013
Petrocca F, Vecchione A, Croce CM (2008b) Emerging role of miR-106b-25/miR-17-92 clusters in the control of transforming growth factor β signaling. Cancer Res 68:8191–8194. https://doi.org/10.1158/0008-5472.CAN-08-1768
Piao J-Y, Lee HG, Kim S-J et al (2016) Helicobacter pylori activates IL-6-STAT3 Signaling in human gastric cancer cells: potential roles for reactive oxygen species. Helicobacter 21:405–416. https://doi.org/10.1111/hel.12298
Radolf JD, Samuels DS (eds) (2021) Lyme disease and relapsing fever spirochetes: genomics, molecular biology, host interactions and disease pathogenesis. Caister Academic Press, Poole
Raingeaud J, Gupta S, Rogers JS et al (1995) Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 270:7420–7426. https://doi.org/10.1074/jbc.270.13.7420
Raingeaud J, Whitmarsh AJ, Barrett T et al (1996) MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol 16:1247–1255. https://doi.org/10.1128/MCB.16.3.1247
Rihane FE, Hassou N, Nadifi S, Ennaji MM (2020) Status of Helicobacter pylori coinfection with Epstein–Barr virus in gastric cancer. In: Ennaji MM (ed) Emerging and reemerging viral pathogens. Elsevier, Amsterdam, pp 571–585
Roberts ML, Cooper NR (1998) Activation of a Ras–MAPK-dependent pathway by Epstein–Barr virus latent membrane protein 1 Is essential for cellular transformation. Virology 240:93–99. https://doi.org/10.1006/viro.1997.8901
Saitoh M (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 17:2596–2606. https://doi.org/10.1093/emboj/17.9.2596
Săsăran MO, Meliț LE, Dobru ED (2021) MicroRNA modulation of host immune response and inflammation triggered by Helicobacter pylori. Int J Mol Sci 22:1406. https://doi.org/10.3390/ijms22031406
Sawai N, Kita M, Kodama T et al (1999) Role of gamma interferon in Helicobacter pylori -induced gastric inflammatory responses in a mouse model. Infect Immun 67:279–285. https://doi.org/10.1128/IAI.67.1.279-285.1999
Schultheiss U (2001) TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1. EMBO J 20:5678–5691. https://doi.org/10.1093/emboj/20.20.5678
Sears R, Nuckolls F, Haura E et al (2000) Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 14:2501–2514. https://doi.org/10.1101/gad.836800
Seif F, Khoshmirsafa M, Aazami H et al (2017) The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal 15:23. https://doi.org/10.1186/s12964-017-0177-y
Seo JH, Lim JW, Kim H, Kim KH (2004) Helicobacter pylori in a Korean isolate activates mitogen-activated protein kinases, AP-1, and NF-κB and induces chemokine expression in gastric epithelial AGS cells. Lab Invest 84:49–62. https://doi.org/10.1038/labinvest.3700010
Sethi G, Sung B, Aggarwal BB (2008) Nuclear factor-κB activation: from bench to bedside. Exp Biol Med 233:21–31. https://doi.org/10.3181/0707-MR-196
Seto E, Moosmann A, Grömminger S et al (2010) Micro RNAs of Epstein–Barr virus promote cell cycle progression and prevent apoptosis of primary human B cells. PLoS Pathog 6:e1001063. https://doi.org/10.1371/journal.ppat.1001063
Sgarbanti M, Marsili G, Remoli AL et al (2007) IRF-7: new role in the regulation of genes involved in adaptive immunity. Ann N Y Acad Sci 1095:325–333. https://doi.org/10.1196/annals.1397.036
Shackelford J, Maier C, Pagano JS (2003) Epstein–Barr virus activates β-catenin in type III latently infected B lymphocyte lines: association with deubiquitinating enzymes. Proc Natl Acad Sci 100:15572–15576. https://doi.org/10.1073/pnas.2636947100
Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4:E131–E136. https://doi.org/10.1038/ncb0502-e131
Sheedy FJ, Palsson-McDermott E, Hennessy EJ et al (2010) Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol 11:141–147. https://doi.org/10.1038/ni.1828
Shi Q, Zhang Y, Liu W et al (2020) Latent membrane protein 2A inhibits expression level of Smad2 through regulating miR-155-5p in EBV-associated gastric cancer cell lines. J Med Virol 92:96–106. https://doi.org/10.1002/jmv.25579
Shin J-Y, Kim J-O, Lee SK et al (2010) LY294002 may overcome 5-FU resistance via down-regulation of activated p-AKT in Epstein–Barr virus-positive gastric cancer cells. BMC Cancer 10:425. https://doi.org/10.1186/1471-2407-10-425
Siegler G (2003) Epstein–Barr virus encoded latent membrane protein 1 (LMP1) and TNF receptor associated factors (TRAF): colocalisation of LMP1 and TRAF1 in primary EBV infection and in EBV associated Hodgkin lymphoma. Mol Pathol 56:156–161. https://doi.org/10.1136/mp.56.3.156
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
Slomiany BL (2012) Helicobacter pylori induction in gastric mucosal prostaglandin and nitric oxide generation is dependent on MAPK/ERK-mediated activation of IKK-β and cPLA2: modulatory effect of ghrelin. Open J Cell Biol 02:21–31. https://doi.org/10.4236/ojcb.2012.22003
Song X, Xin N, Wang W, Zhao C (2015) Wnt/β-catenin, an oncogenic pathway targeted by H. pylori in gastric carcinogenesis. Oncotarget 6:35579–35588. https://doi.org/10.18632/oncotarget.5758
Sonkar C, Kashyap D, Varshney N et al (2020) Impact of gastrointestinal symptoms in COVID-19: a molecular approach. SN Compr Clin Med 2:2658–2669. https://doi.org/10.1007/s42399-020-00619-z
Soutto M, Peng D, Katsha A et al (2015) Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis. Gut 64:1028–1039. https://doi.org/10.1136/gutjnl-2014-307191
Su B, Ceponis PJM, Lebel S et al (2003) Helicobacter pylori activates Toll-like receptor 4 expression in gastrointestinal epithelial cells. Infect Immun 71:3496–3502. https://doi.org/10.1128/IAI.71.6.3496-3502.2003
Suarez F (2006) Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood 107:3034–3044. https://doi.org/10.1182/blood-2005-09-3679
Sun S-C (2011) Non-canonical NF-κB signaling pathway. Cell Res 21:71–85. https://doi.org/10.1038/cr.2010.177
Sun L, Zhao Y, Shi H et al (2015) LMP-1 induces survivin expression to inhibit cell apoptosis through the NF-κB and PI3K/Akt signaling pathways in nasal NK/T-cell lymphoma. Oncol Rep 33:2253–2260. https://doi.org/10.3892/or.2015.3847
Sun Z, Jha HC, Pei Y, Robertson ES (2016) Major histocompatibility complex class II HLA-DRα is downregulated by Kaposi’s sarcoma-associated herpesvirus-encoded lytic transactivator RTA and MARCH8. J Virol 90:8047–8058. https://doi.org/10.1128/JVI.01079-16
Tang B, Xiao B, Liu Z et al (2010) Identification of MyD88 as a novel target of miR-155, involved in negative regulation of Helicobacter pylori-induced inflammation. FEBS Lett 584:1481–1486. https://doi.org/10.1016/j.febslet.2010.02.063
Tang Z, Chen W, Xu Y et al (2020) miR-4721, induced by EBV-miR-BART22, targets GSK3β to enhance the tumorigenic capacity of NPC through the WNT/β-catenin pathway. Mol Ther Nucleic Acids 22:557–571. https://doi.org/10.1016/j.omtn.2020.09.021
Tavakoli A, Monavari SH, Solaymani Mohammadi F et al (2020) Association between Epstein–Barr virus infection and gastric cancer: a systematic review and meta-analysis. BMC Cancer 20:493. https://doi.org/10.1186/s12885-020-07013-x
Tegtmeyer N, Wessler S, Backert S (2011) Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. FEBS J 278:1190–1202. https://doi.org/10.1111/j.1742-4658.2011.08035.x
Toh JWT, Wilson RB (2020) Pathways of gastric carcinogenesis, Helicobacter pylori virulence and interactions with antioxidant systems, vitamin C and phytochemicals. Int J Mol Sci 21:6451. https://doi.org/10.3390/ijms21176451
Torisu T, Kawano S, Miyawaki K et al (2021) B cell receptor signaling related to resistance to Helicobacter pylori eradication therapy in gastric diffuse large B cell lymphoma. Hematol Oncol 39:145–147. https://doi.org/10.1002/hon.2816
Tye H, Kennedy CL, Najdovska M et al (2012) STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 22:466–478. https://doi.org/10.1016/j.ccr.2012.08.010
Uno K (2014) Novel role of toll-like receptors in Helicobacter pylori—induced gastric malignancy. World J Gastroenterol 20:5244. https://doi.org/10.3748/wjg.v20.i18.5244
Valente RM, Ehlers E, Xu D et al (2012) Toll-like receptor 7 stimulates the expression of Epstein–Barr virus latent membrane protein 1. PLoS ONE 7:e43317. https://doi.org/10.1371/journal.pone.0043317
van Zuylen WJ, Rawlinson WD, Ford CE (2016) The Wnt pathway: a key network in cell signalling dysregulated by viruses: Wnt signalling and viral infection. Rev Med Virol 26:340–355. https://doi.org/10.1002/rmv.1892
Vanden Berghe W, Plaisance S, Boone E et al (1998) p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-κB p65 transactivation mediated by tumor necrosis factor. J Biol Chem 273:3285–3290. https://doi.org/10.1074/jbc.273.6.3285
Vaysberg M, Lambert SL, Krams SM, Martinez OM (2009) Activation of the JAK/STAT pathway in Epstein Barr virus+-associated posttransplant lymphoproliferative disease: role of interferon-γ. Am J Transplant 9:2292–2302. https://doi.org/10.1111/j.1600-6143.2009.02781.x
Velapasamy S, Dawson C, Young L et al (2018) The dynamic roles of TGF-β signalling in EBV-associated cancers. Cancers 10:247. https://doi.org/10.3390/cancers10080247
Voigt S, Sterz KR, Giehler F et al (2020) A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation. Nat Commun 11:685. https://doi.org/10.1038/s41467-020-14502-x
Wakisaka N, Kondo S, Yoshizaki T et al (2004) Epstein–Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1α. Mol Cell Biol 24:5223–5234. https://doi.org/10.1128/MCB.24.12.5223-5234.2004
Wan YY, Flavell RA (2008) TGF-β and regulatory T cell in immunity and autoimmunity. J Clin Immunol 28:647–659. https://doi.org/10.1007/s10875-008-9251-y
Wan J, Sun L, Mendoza JW et al (2004) Elucidation of the c-Jun N-terminal kinase pathway mediated by Epstein–Barr virus-encoded latent membrane protein 1. Mol Cell Biol 24:192–199. https://doi.org/10.1128/MCB.24.1.192-199.2004
Wan X-X, Yi H, Qu J-Q et al (2015) Integrated analysis of the differential cellular and EBV miRNA expression profiles in microdissected nasopharyngeal carcinoma and non-cancerous nasopharyngeal tissues. Oncol Rep 34:2585–2601. https://doi.org/10.3892/or.2015.4237
Wang L (2016) Inactivation of type I IFN Jak-STAT pathway in EBV latency. Cancer Biol Treat 3:1–4. https://doi.org/10.24966/CBT-7546/100009
Wang X, Ron D (1996) Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP kinase. Science 272:1347–1349. https://doi.org/10.1126/science.272.5266.1347
Wang J, Ni Z, Duan Z et al (2014) Altered expression of hypoxia-inducible factor-1α (HIF-1α) and its regulatory genes in gastric cancer tissues. PLoS ONE 9:e99835. https://doi.org/10.1371/journal.pone.0099835
Wang F, Liu J, Zou Y et al (2017) MicroRNA-143-3p, up-regulated in H. pylori-positive gastric cancer, suppresses tumor growth, migration and invasion by directly targeting AKT2. Oncotarget 8:28711–28724. https://doi.org/10.18632/oncotarget.15646
Wang M, Gu B, Chen X et al (2019) The function and therapeutic potential of Epstein–Barr virus-encoded MicroRNAs in cancer. Mol Ther Nucleic Acids 17:657–668. https://doi.org/10.1016/j.omtn.2019.07.002
Wang J, Ge J, Wang Y et al (2022) EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1. Nat Commun 13:866. https://doi.org/10.1038/s41467-022-28479-2
Watanabe T, Asano N, Fichtner-Feigl S et al (2010) NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest 120:1645–1662. https://doi.org/10.1172/JCI39481
Watanabe T, Asano N, Kitani A et al (2011) Activation of type I IFN signaling by NOD1 mediates mucosal host defense against Helicobacter pylori infection. Gut Microbes 2:61–65. https://doi.org/10.4161/gmic.2.1.15162
Wen J, Wang Y, Gao C et al (2018a) Helicobacter pylori infection promotes Aquaporin 3 expression via the ROS–HIF-1α–AQP3–ROS loop in stomach mucosa: a potential novel mechanism for cancer pathogenesis. Oncogene 37:3549–3561. https://doi.org/10.1038/s41388-018-0208-1
Wen G, Deng S, Song W et al (2018b) Helicobacter pylori infection downregulates duodenal CFTR and SLC26A6 expressions through TGFβ signaling pathway. BMC Microbiol 18:87. https://doi.org/10.1186/s12866-018-1230-8
Wood VHJ, O’Neil JD, Wei W et al (2007) Epstein–Barr virus-encoded EBNA1 regulates cellular gene transcription and modulates the STAT1 and TGFβ signaling pathways. Oncogene 26:4135–4147. https://doi.org/10.1038/sj.onc.1210496
Wu L, Nakano H, Wu Z (2006) The C-terminal activating region 2 of the Epstein–Barr virus-encoded latent membrane protein 1 activates NF-κB through TRAF6 and TAK1. J Biol Chem 281:2162–2169. https://doi.org/10.1074/jbc.M505903200
Wu M, Lin J, Hsu P et al (2007) Preferential induction of transforming growth factor–β production in gastric epithelial cells and monocytes by Helicobacter pylori soluble proteins. J Infect Dis 196:1386–1393. https://doi.org/10.1086/522520
Ye F, Tang C, Shi W et al (2015) A MDM2-dependent positive-feedback loop is involved in inhibition of miR-375 and miR-106b induced by Helicobacter pylori lipopolysaccharide: H. pylori LPS inhibits miR-375 and miR106b. Int J Cancer 136:2120–2131. https://doi.org/10.1002/ijc.29268
Yin Q, Flemington EK (2006) siRNAs against the Epstein Barr virus latency replication factor, EBNA1, inhibit its function and growth of EBV-dependent tumor cells. Virology 346:385–393. https://doi.org/10.1016/j.virol.2005.11.021
Yin T, Taga T, Tsang ML et al (1950) (1993) Involvement of IL-6 signal transducer gp130 in IL-11-mediated signal transduction. J Immunol Baltim Md 151:2555–2561
Young LS, Dawson CW (2014) Epstein–Barr virus and nasopharyngeal carcinoma. Chin J Cancer. https://doi.org/10.5732/cjc.014.10197
Zauner L (2012) Understanding TLR9 action in Epstein–Barr virus infection. Front Biosci 17:1219. https://doi.org/10.2741/3982
Zervos AS, Faccio L, Gatto JP et al (1995) Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. Proc Natl Acad Sci 92:10531–10534. https://doi.org/10.1073/pnas.92.23.10531
Zhang W, Liu HT (2002) MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res 12:9–18. https://doi.org/10.1038/sj.cr.7290105
Zhang Z, Li Z, Gao C et al (2008) miR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Invest 88:1358–1366. https://doi.org/10.1038/labinvest.2008.94
Zhang W, Han D, Wan P et al (2016) ERK/c-Jun recruits Tet1 to induce Zta expression and Epstein–Barr virus reactivation through DNA demethylation. Sci Rep 6:34543. https://doi.org/10.1038/srep34543
Zhao L, Vogt PK (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486–5496. https://doi.org/10.1038/onc.2008.244
Zheng Z-M (2010) Viral oncogenes, noncoding RNAs, and RNA splicing in human tumor viruses. Int J Biol Sci. https://doi.org/10.7150/ijbs.6.730
Zhou L, Bu Y, Liang Y et al (2016) Epstein–Barr virus (EBV)-BamHI-a rightward transcript (BART)-6 and cellular MicroRNA-142 synergistically compromise immune defense of host cells in EBV-positive burkitt lymphoma. Med Sci Monit 22:4114–4120. https://doi.org/10.12659/MSM.897306
Zhu C, Zhu Q, Wang C et al (2016) Hostile takeover: Manipulation of HIF-1 signaling in pathogen-associated cancers (Review). Int J Oncol 49:1269–1276. https://doi.org/10.3892/ijo.2016.3633
Zwezdaryk KJ, Combs JA, Morris CA, Sullivan DE (2016) Regulation of Wnt/β-catenin signaling by herpesviruses. World J Virol 5:144–154. https://doi.org/10.5501/wjv.v5.i4.144
Acknowledgements
We gratefully acknowledge the DST-FIST Project No. SR/FST/LS-I/2020/621 and Indian Institute of Technology Indore for providing facilities and support. This project was supported by the Department of Science and Technology DST-EMR project no. DST-EMR: EMR/2017/001637. We are thankful to CSIR, UGC, and DBT for fellowship to Dharmendra Kashyap, Pranit Hemant Bagde, and Vaishali Saini respectively in the form of a research stipend. We appreciate Ms. Annu Rani, Dr. Tarun Prakash Verma, Samiksha Rele, Siddharth Singh, Sonali Adhikari, and our other laboratory colleagues for insightful discussions and advice.
Funding
This project was supported by the Department of Science and Technology grant no. DST-EMR: EMR/2017/001637 and Center for Rural Development and Technology, IIT Indore grant no. IITI/CRDT/2022-23/05.
Author information
Authors and Affiliations
Contributions
HCJ and DK contributed to the design, data acquisition, analysis, conceptualization, interpretation, and drafted. VS, PB and SR contributed to the analysis, interpretation, and drafting. DC, AKJ and RKP critically revised the manuscript. All authors gave final approval and agreed to be accountable for all aspects of the work.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest associated with this article.
Ethical approval
Not applicable.
Additional information
Communicated by Yusuf Akhter.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Kashyap, D., Rele, S., Bagde, P.H. et al. Comprehensive insight into altered host cell-signaling cascades upon Helicobacter pylori and Epstein–Barr virus infections in cancer. Arch Microbiol 205, 262 (2023). https://doi.org/10.1007/s00203-023-03598-6
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00203-023-03598-6