title: The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner.
abstract: 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 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.
authors.affiliation: Cancer Research, The Canberra Hospital, Garran, ACT, Australia.
authors.forename: Mhairi
authors.initials: M
authors.lastname: Baird
authors.forename: Pei
authors.initials: P
authors.lastname: Woon Ang
authors.forename: Ian
authors.initials: I
authors.lastname: Clark
authors.forename: Danial
authors.initials: D
authors.lastname: Bishop
authors.forename: Masanobu
authors.initials: M
authors.lastname: Oshima
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: Christine
authors.initials: C
authors.lastname: Hemmings
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takeishi
authors.forename: Dan
authors.initials: D
authors.lastname: Worthley
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Doug
authors.initials: D
authors.lastname: Taupin
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D019872:Chief Cells, Gastric / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005752:Gastric Mucins / Q000737:chemistry / Q000378:metabolism; D005753:Gastric Mucosa / Q000737:chemistry / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016481:Helicobacter Infections / Q000378:metabolism* / Q000473:pathology; D016480:Helicobacter pylori / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008679:Metaplasia / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D000071701:Regulatory Factor X Transcription Factors; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D051742:Transcription Factor CHOP / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D005752:Gastric Mucins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP