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 ¼ 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 Helicobacter pylori (H. pylori) is a major risk factor for human gastric cancer (GC). 1 Sustained interaction between H. pylori and the gastric epithelium induces chronic inflammation and loss of parietal cells (oxyntic atrophy), leading to development of mucous metaplasia (MM)-intestinal metaplasia (IM) and spasmolytic polypeptide expressing metaplasia (SPEM). 2 Studies in human and murine models indicate that IM and SPEM are critical neoplastic precursors in the cascade of gastric carcinogenesis. [3][4][5][6] IM is characterized by the presence of intestinal goblet cells with simultaneous expressions of TFF3 and MUC2 7 while SPEM, named for its characteristic expression of spasmolytic polypeptide (TFF2), expresses MUC6 and resembles deep antral gland cells. 5 Reported studies suggest that SPEM, derived from transdifferentiation of chief cells, 8 gives rise to IM and ultimately dysplasia in the setting of oxyntic atrophy and chronic inflammation. 9 Despite characterization of the sequence and origin of metaplastic mucous cell lineage, the mechanisms responsible for neoplastic transformation of the secretory cell lineage are not understood.Cancer cells are under constant e...

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