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Protein Kinase A (PKAc alpha ) regulates gastric homeostasis and preneoplastic lesions

ABSTRACT: We generated a novel Six2-Cre+/-PKAcaRfl/wt (CA-PKA) CA-PKA mouse in which expression of constitutive-active PKAcaR was induced in gastric mesenchyme progenitors. CA-PKA mice showed disruption of gastric homeostasis characterized by aberrant mucosal development and epithelial hyperproliferation; ultimately developing multiple features of gastric corpus preneoplasia including decreased parietal cells, mucous cell hyperplasia, spasmolytic peptide expressing metaplasia (SPEM) with intestinal characteristics and dysplastic and invasive cystic glands. Our results show that constitutively active PKAcaR in the stomach mesenchyme nonautonomously disrupts gastric homeostasis characterized by increased epithelial proliferation and aberrant epithelial maldevelopment, ultimately leading to gastric preneoplasia.

ORGANISM(S): Mus musculus

PROVIDER: GSE196236 | GEO | 2022/09/20

REPOSITORIES: GEO

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Transplantation of gastric organoid-derived spasmolytic polypeptide/TFF2-expressing metaplasia (SPEM) cell lineage promotes ulcer repair in the aged stomach

Project description:Background & Aims: Spasmolytic polypeptide/TFF2-expressing metaplasia (SPEM) is known to emerge following parietal cell loss and during Helicobacter pylori infection, however its role in gastric ulcer repair is unknown. Therefore, we sought to investigate if SPEM plays a role in epithelial regeneration. Methods: Acetic acid ulcers were induced in young (2-3 months) C57BL/6 mice to determine the quality of ulcer repair. Gastric tissue was collected and analyzed to determine the expression of SPEM within the regenerating epithelium. As a comparison to native tissue the expression of SPEM was also identified within cultured gastric mouse-derived organoids. Results: Wound healing in the mice coincided with the emergence of SPEM expressing CD44v within the ulcerated region. The emergence of SPEM was also observed in cultured gastric organoids. Conclusions: These data demonstrate the SPEM may play a role in epithelial regeneration. Conclusions: These data demonstrate the SPEM may play a role in epithelial regeneration. 4 samples were used for ulcerated and uninjured tissue. 1 sample was used for intact tissue and organoid-derived RNA. The 'Ulcerated' samples represent C57BL/6 mice with ulcers and the 'Uninjured' samples represent the healthy controls (for "ulcerated" samples). The "Intact stomach tissue" and "Gastric organoids" samples are other types of samples that compared separately. "Gastric organoids" in this comparison are derived from "Intact stomach tissue".

2015-09-23 | E-GEOD-73336 | biostudies-arrayexpress

Transplantation of gastric organoid-derived spasmolytic polypeptide/TFF2-expressing metaplasia (SPEM) cell lineage promotes ulcer repair in the aged stomach

2015-09-23 | GSE73336 | GEO

Tristetraprolin prevents gastric metaplasia by suppressing pathogenic inflammation

Project description:Purpose: The goals of this study are to examine whether TTP can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM). Methods: we utilized the TTP∆ARE mouse model to examine whether TTP overexpression can protect the stomach from adrenalectomy (ADX)-induced gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM). Results: We found that TTP∆ARE mice were completely protected from ADX-induce gastric inflammation and SPEM. RNA sequencing revealed that TTP overexpression suppressed the expression of genes associated with the innate immune response. Finally, we show that protection from gastric inflammation was only partially due to suppression of Tnf, a well-known TTP target. Conclusions: Our results demonstrate that TTP exerts broad anti-inflammatory effects in the stomach, and suggest that therapies that increase TTP expression may be effective treatments of pro-neoplastic gastric inflammation.

2021-11-10 | GSE164349 | GEO

Effects of a gastrin receptor antagonist (NTZ, previously named YF) on the gastric corpus mucosa of HKATPase betasubunit knockout (KO) mice

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2019-12-23 | GSE142513 | GEO

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2019-03-20 | GSE107736 | GEO

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2017-01-20 | GSE77195 | GEO

YAP-activated metaplasia underlies gastric adenocarcinoma and corpus regenerative mechanisms [RNA-Seq]

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2023-11-07 | GSE199171 | GEO

YAP-activated metaplasia underlies gastric adenocarcinoma and corpus regenerative mechanisms [ChIP-Seq]

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A Point Mutation R122C in RUNX3 Promotes the Expansion of Isthmus Stem Cells and Inhibits Their Differentiation in the Stomach

Project description:Background & Aims: RUNX transcription factors play pivotal roles in embryonic development and neoplasia. We previously identified the single missense mutation R122C in RUNX3 from human gastric cancer. However, how RUNX3R122C mutation disrupts stem cell homeostasis and promotes gastric carcinogenesis remained unclear. Methods: To understand the oncogenic nature of this mutation in vivo, we generated the RUNX3R122C knock-in mice. Stomach tissues were harvested, followed by histological and immunofluorescence staining, organoid culture, flow cytometry to isolate gastric corpus isthmal and non-isthmal epithelial cells, and RNA extraction for transcriptomic analysis. Results: The corpus tissue of RUNX3R122C/R122C homozygous mice exhibited a precancerous phenotype such as spasmolytic polypeptide-expressing metaplasia (SPEM). We observed mucous neck cell hyperplasia, massive reduction of pit, parietal, and chief cell populations, as well as a dramatic increase in the number of rapidly proliferating isthmal stem/progenitor cells in the corpus of RUNX3R122C/R122C mice. Transcriptomic analyses of the isolated epithelial cells showed that the cell cycle-related MYC target gene signature was enriched in the corpus epithelial cells of RUNX3R122C/R122C mice compared with the wild-type corpus. Mechanistically, RUNX3R122C mutant protein disrupted the regulation of the restriction point where cells decide to enter either proliferative or quiescent state, thereby driving stem cell expansion and limiting the ability of cells to terminally differentiate. Conclusions: RUNX3R122C missense mutation is associated with the continuous cycling of isthmal stem/progenitor cells, maturation arrest and development of a precancerous state. This work highlights the importance of RUNX3 in prevention of metaplasia and gastric cancer.

2021-12-05 | GSE190081 | GEO

A Point Mutation R122C in RUNX3 Promotes the Expansion of Isthmus Stem Cells and Inhibits Their Differentiation in the Stomach

2021-12-13 | GSE190506 | GEO

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