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Transcriptome analysis of MET-constitutively active versus MET-silenced colorectal cancer cells

ABSTRACT: To investigate the expression patterns driven by hyperactivated MET in MET-dependent cells, we employed LoVo colon adenocarcinoma cell line, harbouring a post-translational modification of MET that leads to its constitutive activation. We then silenced MET in LoVo cells using CRISPR/Cas9 knock-out (KO) protocol, and performed gene expression profiling analysis using data obtained from RNA-seq of cells with hyperactivated-MET versus MET-KO.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212835 | GEO | 2023/10/14

REPOSITORIES: GEO

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Project description: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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Transcriptome analysis of MET-constitutively active versus MET-silenced colorectal cancer cells

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