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http://purl.uniprot.org/citations/34391772http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/34391772http://www.w3.org/2000/01/rdf-schema#comment"

Background & aims

Metaplasia and dysplasia in the corpus are reportedly derived from de-differentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C (PGC) transcript-expressing cells represent the cellular origin of metaplasia and cancer using a novel Pgc-specific CreERT2 recombinase mouse model.

Methods

We generated a Pgc-mCherry-IRES-CreERT2 (Pgc-CreERT2) knock-in mouse model. Pgc-CreERT2/+ and Rosa-EYFP mice were crossed to generate Pgc-CreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments and histologic and immunofluorescence staining. We further established Pgc-CreERT2;KrasG12D/+ mice and investigated whether PGC transcript-expressing cells are responsible for the precancerous state in gastric glands. To investigate cancer development from PGC transcript-expressing cells with activated Kras, inactivated Apc, and Trp53 signaling pathways, we crossed Pgc-CreERT2/+ mice with conditional KrasG12D, Apcflox, Trp53flox mice.

Results

Expectedly, mCherry mainly labeled chief cells in the Pgc-CreERT2 mice. However, mCherry was also detected throughout the neck cell and isthmal stem/progenitor regions, albeit at lower levels. In the Pgc-CreERT2;KrasG12D/+ mice, PGC transcript-expressing cells with KrasG12D/+ mutation presented pseudopyloric metaplasia. The early induction of proliferation at the isthmus may reflect the ability of isthmal progenitors to react rapidly to Pgc-driven KrasG12D/+ oncogenic mutation. Furthermore, Pgc-CreERT2;KrasG12D/+;Apcflox/flox mice presented intramucosal dysplasia/carcinoma and Pgc-CreERT2;KrasG12D/+;Apcflox/flox;Trp53flox/flox mice presented invasive and metastatic gastric carcinoma.

Conclusions

The Pgc-CreERT2 knock-in mouse is an invaluable tool to study the effects of successive oncogenic activation in the mouse corpus. Time-course observations can be made regarding the responses of isthmal and chief cells to oncogenic insults. We can observe stomach-specific tumorigenesis from the beginning to metastatic development."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.org/dc/terms/identifier"doi:10.1053/j.gastro.2021.08.013"xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Abe T."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Chen S."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Ito Y."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Pang S."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Shimura M."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Unno M."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Yeoh K.G."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Yamamura A."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Kim G."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Srivastava S."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Suda K."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Shioi G."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Kohu K."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Shabbir A."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Matsuo J."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Douchi D."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Teh M."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Chuang L.S.H."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Nuttonmanit N."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Bok-Yan So J."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/author"Melissa Lim Y.H."xsd:string
http://purl.uniprot.org/citations/34391772http://purl.uniprot.org/core/date"2021"xsd:gYear
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