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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Feb 17, 2021 |
| Title |
Induction of gastric cancer by successive oncogenic activation in the corpus |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background & 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 Ctranscript 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 PgcCreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments, histological and immunofluorescence staining. We further established Pgc-CreERT2;Kras G12D/+ mice and investigated whether PGCtranscript 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 , Trp53 flox 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;Kras G12D/+ mice, PGC-transcript expressing cells with Kras G12D/+ 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 Kras G12D/+ oncogenic mutation. Furthermore, Pgc-CreERT2;KrasG12D/+ ;Apc flox/flox mice presented intramucosal dysplasia/carcinoma, while Pgc-CreERT2;KrasG12D/+ ;Apcflox/flox ;Trp53 flox/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.
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| Overall design |
RNA expression profile of stomach corpus of PGC;Ras;APC FF mice or Control (Ras;APC FF) mice. Total RNA was extracted from the corpus tissue. Triplicate samples are shown.
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| Contributor(s) |
Douchi D, Yamamura A, Matsuo J, Lim YH, Nuttonmanit N, Shimura M, Suda K, Chen S, Pang S, Kohu K, Abe T, Shioi G, Kim G, Shabbir A, Srivastava S, Unno M, So JB, Teh M, Yeoh KG, Chuang LS, Ito Y |
| Citation(s) |
34391772 |
| Submission date |
Feb 16, 2021 |
| Last update date |
Sep 08, 2021 |
| Contact name |
Daisuke Douchi |
| E-mail(s) |
d.douchi@surg.med.tohoku.ac.jp
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| Phone |
+65-92476620
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| Organization name |
Cancer Science Institute of Singapore
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| Department |
Centre for Translational Medicine
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| Street address |
14 Medical Drive
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| City |
Singapore |
| ZIP/Postal code |
117599 |
| Country |
Singapore |
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| Platforms (1) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA702205 |
| SRA |
SRP306767 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE166904_PGC_GEO_Gene.FPKM.txt.gz |
264.7 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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