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dc.contributor.authorPeterson, Anthony J.
dc.contributor.authorMenheniott, Trevelyan R.
dc.contributor.authorO'Connor, Louise
dc.contributor.authorWalduck, Anna K.
dc.contributor.authorFox, James G.
dc.contributor.authorKawakami, Kazuyuki
dc.contributor.authorMinamoto, Toshinari
dc.contributor.authorOng, Eng Kok
dc.contributor.authorWang, Timothy C.
dc.contributor.authorJudd, Louise M.
dc.contributor.authorGiraud, Andrew S.
dc.date.accessioned2015-10-20T13:13:34Z
dc.date.available2015-10-20T13:13:34Z
dc.date.issued2010-08
dc.date.submitted2010-02
dc.identifier.issn00165085
dc.identifier.issn1528-0012
dc.identifier.urihttp://hdl.handle.net/1721.1/99371
dc.description.abstractBackground & Aims Trefoil factors (TFFs) regulate mucosal repair and suppress tumor formation in the stomach. Tff1 deficiency results in gastric cancer, whereas Tff2 deficiency increases gastric inflammation. TFF2 expression is frequently lost in gastric neoplasms, but the nature of the silencing mechanism and associated impact on tumorigenesis have not been determined. Methods We investigated the epigenetic silencing of TFF2 in gastric biopsy specimens from individuals with Helicobacter pylori-positive gastritis, intestinal metaplasia, gastric cancer, and disease-free controls. TFF2 function and methylation were manipulated in gastric cancer cell lines. The effects of Tff2 deficiency on tumor growth were investigated in the gp130[superscript F/F] mouse model of gastric cancer. Results In human tissue samples, DNA methylation at the TFF2 promoter began at the time of H pylori infection and increased throughout gastric tumor progression. TFF2 methylation levels were inversely correlated with TFF2 messenger RNA levels and could be used to discriminate between disease-free controls, H pylori-infected, and tumor tissues. Genome demethylation restored TFF2 expression in gastric cancer cell lines, so TFF2 silencing requires methylation. In Tff2-deficient gp130[superscript F/F]/Tff2[superscript −/−] mice, proliferation of mucosal cells and release of T helper cell type-1 (Th-1) 1 cytokines increased, whereas expression of gastric tumor suppressor genes and Th-2 cytokines were reduced, compared with gp130[superscript F/F]controls. The fundus of gp130[superscript F/F]/Tff2[superscript −/−] mice displayed glandular atrophy and metaplasia, indicating accelerated preneoplasia. Experimental H pylori infection in wild-type mice reduced antral expression of Tff2 by increased promoter methylation. Conclusions TFF2 negatively regulates preneoplastic progression and subsequent tumor development in the stomach, a role that is subverted by promoter methylation during H pylori infection.en_US
dc.description.sponsorshipNational Health and Medical Research Council (Australia)en_US
dc.language.isoen_US
dc.publisherElsevieren_US
dc.relation.isversionofhttp://dx.doi.org/10.1053/j.gastro.2010.08.043en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.sourcePMCen_US
dc.titleHelicobacter pylori Infection Promotes Methylation and Silencing of Trefoil Factor 2, Leading to Gastric Tumor Development in Mice and Humansen_US
dc.typeArticleen_US
dc.identifier.citationPeterson, Anthony J., Trevelyan R. Menheniott, Louise O’Connor, Anna K. Walduck, James G. Fox, Kazuyuki Kawakami, Toshinari Minamoto, et al. “Helicobacter Pylori Infection Promotes Methylation and Silencing of Trefoil Factor 2, Leading to Gastric Tumor Development in Mice and Humans.” Gastroenterology 139, no. 6 (December 2010): 2005–2017.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Division of Comparative Medicineen_US
dc.contributor.mitauthorFox, James G.en_US
dc.relation.journalGastroenterologyen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsPeterson, Anthony J.; Menheniott, Trevelyan R.; O'Connor, Louise; Walduck, Anna K.; Fox, James G.; Kawakami, Kazuyuki; Minamoto, Toshinari; Ong, Eng Kok; Wang, Timothy C.; Judd, Louise M.; Giraud, Andrew S.en_US
dc.identifier.orcidhttps://orcid.org/0000-0001-9307-6116
mit.licensePUBLISHER_CCen_US


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