Yes-Associated Protein Drives Helicobacter pylori-Induced Metaplastic Changes in Gastric Epithelium.

BACKGROUND & AIMS: Helicobactor pylori infection triggers a spectrum of metaplastic changes in the gastric epithelium; however, the upstream regulatory mechanisms remain unclear. In human gastric epithelial models, H pylori cytotoxin-associated gene A-dependent signaling stabilized and activated yes-associated protein, thereby promoting metaplastic reprogramming of the gastric epithelium.

METHODS

Human gastric tissue specimens were obtained from patients at Severance Hospital, Yonsei University College of Medicine. Human gastric epithelial cell lines (AGS, MKN74, N87, KATO III) and 8- to 10-week-old C57BL/6J mice were used. Transcriptomic analysis, immunoprecipitation, histologic and immunofluorescence staining, and molecular assays (Western blotting and quantitative reverse-transcription polymerase chain reaction) were performed to assess yes-associated protein signaling and metaplastic marker expression.

RESULTS

Genetic and pharmacologic modulation of yes-associated protein and OTU deubiquitinase, ubiquitin aldehyde binding 2 demonstrated that these metaplastic marker alterations are yes-associated protein-dependent. In vivo, comparative infection with H pylori with or without cytotoxin-associated gene A revealed significantly increased spasmolytic polypeptide-expressing metaplasia markers from chief cells (Griffonia simplicifolia II lectin/gastric intrinsic factor, CD44 variant 9), parietal cell loss, and an expanded proliferative region in the presence of cytotoxin-associated gene A. Helicobacter felis infection was used to broaden the dynamic range of in vivo pathologic outcomes. Manipulating yes-associated protein specifically in chief cells with a muscle, intestine, stomach expression 1 driver verified both the induction and suppression of these lesions, and the administration of recombinant OTU deubiquitinase, ubiquitin aldehyde binding 2 and treatment with selective inhibitors enhanced and reduced metaplastic signaling, respectively.

CONCLUSIONS

Yes-associated protein acts as a central regulator of H pylori-induced metaplastic transformation by reprogramming gastric epithelial and chief cell lineages. OTU deubiquitinase, ubiquitin aldehyde binding 2 serves as an upstream modulator that reinforces yes-associated protein stability and signaling, highlighting yes-associated protein as a potential therapeutic target for preventing metaplastic progression.