Please use this identifier to cite or link to this item: https://doi.org/10.1053/j.gastro.2021.08.013
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dc.titleInduction of gastric cancer by successive oncogenic activation in the corpus.
dc.contributor.authorDouchi, Daisuke
dc.contributor.authorAKIHIRO YAMAMURA
dc.contributor.authorJUNICHI MATSUO
dc.contributor.authorLIM YI HUI MELISSA
dc.contributor.authorNAPAT NUTTONMANIT
dc.contributor.authorMITSUHIRO SHIMURA
dc.contributor.authorKAZUTO SUDA
dc.contributor.authorSABIRAH CHEN XI BTE MUHD FIRDAUS TAN CJ
dc.contributor.authorPANG SHUCHIN
dc.contributor.authorKAZUYOSHI KOFU
dc.contributor.authorAbe, Takaya
dc.contributor.authorShioi, Go
dc.contributor.authorGUOWEI KIM
dc.contributor.authorASIM SHABBIR
dc.contributor.authorSupriya Srivastava
dc.contributor.authorUnno, Michiaki
dc.contributor.authorSO BOK YAN,JIMMY
dc.contributor.authorTEH MING
dc.contributor.authorYEOH KHAY GUAN
dc.contributor.authorCHUANG SHYUE HUEY LINDA
dc.contributor.authorITO,YOSHIAKI
dc.date.accessioned2021-08-23T01:15:46Z
dc.date.available2021-08-23T01:15:46Z
dc.date.issued2021-08-12
dc.identifier.citationDouchi, Daisuke, AKIHIRO YAMAMURA, JUNICHI MATSUO, LIM YI HUI MELISSA, NAPAT NUTTONMANIT, MITSUHIRO SHIMURA, KAZUTO SUDA, SABIRAH CHEN XI BTE MUHD FIRDAUS TAN CJ, PANG SHUCHIN, KAZUYOSHI KOFU, Abe, Takaya, Shioi, Go, GUOWEI KIM, ASIM SHABBIR, Supriya Srivastava, Unno, Michiaki, SO BOK YAN,JIMMY, TEH MING, YEOH KHAY GUAN, CHUANG SHYUE HUEY LINDA, ITO,YOSHIAKI (2021-08-12). Induction of gastric cancer by successive oncogenic activation in the corpus.. Gastroenterology. ScholarBank@NUS Repository. https://doi.org/10.1053/j.gastro.2021.08.013
dc.identifier.issn0016-5085
dc.identifier.issn1528-0012
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/198495
dc.description.abstractBACKGROUND & AIMS: Metaplasia and dysplasia in the corpus are reportedly derived from dedifferentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C-transcript expressing cells (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, histological 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, while 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.
dc.publisherElsevier BV
dc.sourceElements
dc.subjectGastric Carcinogenesis
dc.subjectIntramucosal Dysplasia
dc.subjectInvasive and Metastatic Gastric Cancer
dc.subjectMetaplasia
dc.subjectMouse Model
dc.typeArticle
dc.date.updated2021-08-20T09:32:54Z
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.contributor.departmentDEPT OF MEDICINE
dc.contributor.departmentDEPT OF PATHOLOGY
dc.description.doi10.1053/j.gastro.2021.08.013
dc.description.sourcetitleGastroenterology
dc.published.stateUnpublished
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