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

Mhairi Baird1, Pei Woon Ang, Ian Clark

  • 1Cancer Research, The Canberra Hospital, Garran, ACT, Australia.

Laboratory Investigation; a Journal of Technical Methods and Pathology
|October 31, 2012
PubMed

Insights

Helicobacter pylori infection induces endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in gastric metaplasia, potentially promoting cancer development. HSPA5 is overexpressed in gastric cancer and metaplasia linked to H. pylori.

Area of Science:

  • Gastroenterology
  • Oncology
  • Molecular Biology

Background:

  • Mucous metaplasia (MM) is linked to Helicobacter pylori-induced gastric carcinogenesis.
  • HSPA5, a modulator of the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress, is overexpressed in gastric cancer (GC).

Purpose of the Study:

  • To investigate the activation of the UPR in MM and GC in human and mouse models.
  • To assess the role of H. pylori infection in UPR activation during gastric carcinogenesis.

Main Methods:

  • Assessed RNA and protein levels of ER stress markers (HSPA5, XBP1, CHOP) in human GC and correlated with H. pylori status.
  • Surveyed HSPA5 expression in normal gastric mucosa, gastritis, and intestinal metaplasia (IM).
  • Evaluated UPR markers in mouse models of gastric dysplasia and H. pylori infection.

Main Results:

  • HSPA5 was overexpressed in 33% of human GC cases and in MM associated with H. pylori infection.
  • H. pylori-associated GC showed increased HSPA5 and XBP1 splicing, although CagA-positive H. pylori suppressed these markers in cell culture.
  • Chronic H. felis infection in mice led to increased Hspa5 and Chop expression in dysplasia, unlike spontaneous dysplasia lacking MIST1 expression.

Conclusions:

  • Induction of the UPR in the context of H. pylori-induced chronic inflammation and MM may promote neoplastic transformation.
  • HSPA5 expression and UPR activation are implicated in the pathogenesis of H. pylori-associated gastric cancer.

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