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Type: Journal article
Title: The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner
Author: Baird, M.
Ang, P.
Clark, I.
Bishop, D.
Oshima, M.
Cook, M.
Hemmings, C.
Takeishi, S.
Worthley, D.
Boussioutas, A.
Wang, T.
Taupin, D.
Citation: Laboratory Investigation, 2013; 93(1):112-122
Publisher: Nature Publishing Group
Issue Date: 2013
ISSN: 0023-6837
Statement of
Mhairi Baird, Pei Woon Ang, Ian Clark, Danial Bishop, Masanobu Oshima, Matthew C Cook, Christine Hemmings, Shigeo Takeishi, Dan Worthley, Alex Boussioutas, Timothy C Wang and Doug Taupin
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.
Keywords: Endoplasmic reticulum stress; germfree; mucous metaplasia; unfolded protein response
Rights: © 2013 USCAP, Inc All rights reserved
DOI: 10.1038/labinvest.2012.131
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