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The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner

Baird, Mhairi; Ang, Pei Woon; Clark, Ian; Bishop, Danial; Oshima, Masanobu; Cook, Matthew C; Hemmings, Christine; Takeishi, Shigeo; Worthley, Dan; Boussioutas, Alex; Wang, Timothy C; Taupin, Doug

Description

Mucous metaplasia (MM) is an aberrant secretory phenotype that arises during Helicobacter-induced gastric carcinogenesis. HSPA5, a key modulator of the unfolded protein response (UPR) activated by endoplasmic reticulum (ER) stress is overexpressed in gastric cancer (GC). We studied activation of the UPR in MM and GC in humans and mice. We assessed RNA and protein levels of ER stress markers (HSPA5, XBP1, and CHOP) in human GC, and correlated with Helicobacter pylori (H. pylori) status, then...[Show more]

dc.contributor.authorBaird, Mhairi
dc.contributor.authorAng, Pei Woon
dc.contributor.authorClark, Ian
dc.contributor.authorBishop, Danial
dc.contributor.authorOshima, Masanobu
dc.contributor.authorCook, Matthew C
dc.contributor.authorHemmings, Christine
dc.contributor.authorTakeishi, Shigeo
dc.contributor.authorWorthley, Dan
dc.contributor.authorBoussioutas, Alex
dc.contributor.authorWang, Timothy C
dc.contributor.authorTaupin, Doug
dc.date.accessioned2014-02-21T03:06:32Z
dc.date.available2014-02-21T03:06:32Z
dc.identifier.issn0023-6837
dc.identifier.urihttp://hdl.handle.net/1885/11407
dc.description.abstractMucous metaplasia (MM) is an aberrant secretory phenotype that arises during Helicobacter-induced gastric carcinogenesis. HSPA5, a key modulator of the unfolded protein response (UPR) activated by endoplasmic reticulum (ER) stress is overexpressed in gastric cancer (GC). We studied activation of the UPR in MM and GC in humans and mice. We assessed RNA and protein levels of ER stress markers (HSPA5, XBP1, and CHOP) in human GC, and correlated with Helicobacter pylori (H. pylori) status, then surveyed HSPA5 in normal gastric mucosa and gastric pre-neoplasia including gastritis and intestinal metaplasia (IM). The role of H. pylori infection in the UPR was assessed by co-culture with AGS GC cells. ER stress markers in metaplasia and dysplasia from transgenic K19-Wnt1/C2mE mice and C57Bl/6 mice with chronic Helicobacter felis (H. felis) infection were compared. HSPA5 was overexpressed in 24/73 (33%) of human GC. Induction of HSPA5 and XBP1 splicing was associated with H. pylori-associated GC (P=0.007 for XBP1 splicing). HSPA5 was overexpressed in MM but not gastritis in patients with H. pylori infection. Stimulation of AGS cells with CagA-positive H. pylori suppressed HSPA5 expression and XBP1 splicing. In the normal gastric mucosa of human and mouse, HSPA5 was constitutively expressed in MIST1-positive chief cells. Increased Hspa5 and Chop expression were found in dysplasia of C57Bl/6 mice with chronic H. felis infection but was absent in spontaneous gastric dysplasia in K19-Wnt1/C2mE mice with concomitant loss of Mist1 expression, similar to that observed in H. pylori-associated human GC. Induction of the UPR in the milieu of Helicobacter-induced chronic inflammation and MM may promote neoplastic transformation of Helicobacter-infected gastric mucosa.
dc.description.sponsorshipThis work was supported by grants from the National Health and Medical Research Council (DT), the Canberra Hospital Radiation Oncology Trust Fund (DT), the Canberra Region Medical Foundation (DT), and ESA International (DT).
dc.format11 pages
dc.publisherNature Publishing Group
dc.rightshttp://www.sherpa.ac.uk/romeo/issn/0023-6837/author can archive pre-print (ie pre-refereeing); subject to 6 mth embargo, author can archive post-print (ie final draft post-refereeing); author cannot archive publisher's version/PDF
dc.sourceLaboratory Investigation 93.1 (2013): 112-122
dc.subjectendoplasmic reticulum stress
dc.subjectgermfree
dc.subjectmucous metaplasia
dc.subjectunfolded protein response
dc.titleThe unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner
dc.typeJournal article
local.identifier.citationvolume93
dcterms.dateAccepted2012-07-19
dc.date.issued2013-01
local.identifier.absfor110202 - Haematology
local.identifier.ariespublicationu4971216xPUB149
local.publisher.urlhttp://www.nature.com/
local.type.statusPublished Version
local.contributor.affiliationCook, Matthew C, Australian National University Medical School
local.bibliographicCitation.issue1
local.bibliographicCitation.startpage112
local.bibliographicCitation.lastpage122
local.identifier.doi10.1038/labinvest.2012.131
dc.date.updated2015-12-08T10:46:06Z
local.identifier.scopusID2-s2.0-84871741862
local.identifier.thomsonID000312893200010
CollectionsANU Research Publications

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