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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 28, 2018 |
| Title |
TCPOBOP-induced hepatomegaly & hepatocyte proliferation is attenuated by combined disruption of MET & EGFR signaling in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
TCPOBOP (1,4-Bis [2-(3,5-Dichloropyridyloxy)] benzene) is a constitutive androstane receptor (CAR) agonist that induces robust hepatocyte proliferation and hepatomegaly without any liver injury or tissue loss. TCPOBOP-induced direct hyperplasia has been considered to be CAR-dependent with no evidence of involvement of cytokines or growth factor signaling. Receptor tyrosine kinases (RTKs), MET and EGFR, are known to play a critical role in liver regeneration after partial hepatectomy, but their role in TCPOBOP-induced direct hyperplasia, not yet explored, is investigated in the current study. Disruption of the RTK-mediated signaling was achieved utilizing MET KO mice along with Canertinib treatment for EGFR inhibition. Combined elimination of MET and EGFR signaling [MET KO + EGFRi], but not individual disruption, dramatically reduced TCPOBOP-induced hepatomegaly and hepatocyte proliferation. TCPOBOP-driven CAR activation was not altered in [MET KO + EGFRi] mice, as measured by nuclear CAR translocation and analysis of typical CAR target genes. However, TCPOBOP induced cell cycle activation was impaired in [MET KO + EGFRi] mice due to defective induction of cyclins, which regulate cell cycle initiation and progression. TCPOBOP-driven induction of FOXM1, a key transcriptional regulator of cell cycle progression during TCPOBOP-mediated hepatocyte proliferation, was greatly attenuated in [MET KO + EGFRi] mice. Interestingly, TCPOBOP treatment caused transient decline in HNF4α expression concomitant to proliferative response; this was not seen in [MET KO + EGFRi] mice. Transcriptomic profiling revealed vast majority (~40%) of TCPOBOP-dependent genes mainly related to proliferative response, but not to drug metabolism, were differentially expressed in [MET KO + EGFRi] mice. Conclusion: Taken together, combined disruption of EGFR and MET signaling lead to dramatic impairment of TCPOBOP-induced proliferative response without altering CAR activation.
We used microarrays to detail the global programme of gene expression in [METKO + EGFRi] mice liver following TCPOBOP treatment
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| Overall design |
Systemic inhibition MET-EGFR signaling pathway in mice was carried out by using a tamoxifen inducible system to systemically delete MET and EGFR was inhibited by using Canertinib added to diet. TCPOBOP was administered at Day 0 and liver tissue harvested at defined time points and gene arrays carried out.
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| Contributor(s) |
Bhushan B, Michalopoulos GK |
| Citation(s) |
29888801 |
| Submission date |
Feb 15, 2018 |
| Last update date |
Feb 11, 2019 |
| Contact name |
George K Michalopoulos |
| E-mail(s) |
michalopoulosgk@upmc.edu
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| Organization name |
University of Pittsburgh
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| Street address |
411 SBST, 200 Lothrop Street
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| City |
Pittsburgh |
| State/province |
Pennsylvania |
| ZIP/Postal code |
15261 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (8)
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| GSM3014594 |
Liver tissue from corn oil treated MET flox mice at Day 0 after TCPOBOP administration |
| GSM3014595 |
Liver tissue from Canertinib treated MET KO mice at Day 0 after TCPOBOP administration |
| GSM3014596 |
Liver tissue from corn oil treated MET flox mice at Day 1 after TCPOBOP administration |
| GSM3014597 |
Liver tissue from Canertinib treated MET KO mice at Day 1 after TCPOBOP administration |
| GSM3014598 |
Liver tissue from corn oil treated MET flox mice at Day 2 after TCPOBOP administration |
| GSM3014599 |
Liver tissue from Canertinib treated MET KO mice at Day 2 after TCPOBOP administration |
| GSM3014600 |
Liver tissue from corn oil treated MET flox mice at Day 5 after TCPOBOP administration |
| GSM3014601 |
Liver tissue from Canertinib treated MET KO mice at Day 5 after TCPOBOP administration |
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| Relations |
| BioProject |
PRJNA434289 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE110695_RAW.tar |
33.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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