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TWO DIFFERENT ROLES OF THE CHROMATIN REMODELING COMPONENT ARID1A IN NEOPLASTIC TRANSFORMATION OF GASTRIC MUCOSA

Date
May 21, 2024

Background: Gastric cancer arises within a sequential carcinogenic process from metaplasia to dysplasia and adenocarcinoma. It is known that Kras activation in chief cells recapitulates gastric carcinogenesis observed in patients with gastric cancer. In the corpus, major cell types are chief, parietal, surface, neck, and isthmic progenitor cells. The antrum is primarily composed of surface cells and deep antral gland cells including antral stem cells. Gastric intrinsic factor (Gif) is a stomach-specific gene and is expressed in mouse gastric chief cells. We have recently observed that the Gif is also present in some deep antral stem cells. Arid1a is a key subunit of the SWI/SNF chromatin remodeling complex and regulates gene transcription in cells. Aberrant expression of chromatin remodeling complexes causes abnormal chromatin remodeling and gene transcription in cancer cells. We have therefore examined whether the abnormal chromatin remodeling through Arid1a is involved in gastric cancer development.
Methods: To examine mucosal changes, we established a novel mouse model that simultaneously induces Arid1a knockout (KO) and Kras activation in gastric chief cells and antral stem cells. We utilized the Gif-rtTA; TetO-Cre; KrasG12D/+ (GCK) and Gif-rtTA; TetO-Cre; KrasG12D/+; Arid1afl/fl (GCK-Arid1aKO) mouse alleles. The GCK or GCK-Arid1aKO mice were sacrificed at 2 to 24 weeks after the doxycycline treatment and immunostaining was performed to examine changes in both stomach corpus and antrum.
Results: The GCK-Arid1aKO stomachs normally developed pyloric metaplasia positive for CD44v9 within 2 weeks in corpus and progressed to intestinal metaplasia (IM) positive for TFF3 at 6 weeks. However, the metaplastic glands did not progress to dysplasia at 10 weeks, while the GCK stomachs displayed dysplasia positive for dysplastic cell markers, TROP2 and SCD1. In particular, PDX1, associated with the progression of metaplasia, was downregulated in the GCK-Arid1aKO corpus, suggesting that Pdx1 might be a key downstream factor regulated by Arid1a and the loss of PDX1 expression impeded the metaplasia progression to dysplasia. In contrast, the GCK-Arid1aKO mice showed hyperplastic tumor formation in the antrum with severe fibrotic changes at 24 weeks, while the GCK stomachs did not develop any tumors in the antrum.
Conclusions: Our study suggests that the Arid1a in two different types of gastric cells, gastric chief cells and antral stem cells, can independently lead to the metaplasia progression in the corpus or tumorigenesis in the antrum.

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Speaker Image for Eunyoung Choi
Vanderbilt Unversity Medical Center

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