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High frequency of β-catenin mutations in mouse HCCs induced by a non-genotoxic CAR agonist

ABSTRACT: Activation of Wnt/β-catenin signaling is frequent in human and rodent hepatocarcinogenesis. Although in mice, the tumor promoting activity of agonists of constitutive androstane receptor (CAR) occurs via selection of carcinogen-initiated cells harbouring β-catenin mutations, the molecular alterations leading to hepatocellular carcinoma (HCC) development by The CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), in the absence of genotoxic injury are unknown. Here we show that CAR activation per se induced HCC in mice and that 91% of them carried β-catenin point mutations or large in-frame deletions/exon skipping targeting Ctnnb1 exon 3. Point mutations in HCCs induced by TCPOBOP alone displayed different nucleotide substitutions compared to those found in HCCs from mice pre-treated with diethylnitrosamine (DENA). Moreover, unlike those occurring in HCCs from DENA+TCPOBOP mice, they did not result in increased expression of β-catenin target genes, such as Glul, Lgr5, Rgn, Lect2 and Ccnd1, or nuclear translocation of β-catenin when compared to the control liver. Remarkably, in the non-tumoral liver tissue, chronic CAR activation led to down-regulation of these genes and to a partial loss of glutamine synthetase (GS)-positive hepatocytes. These results thus show that while chronic CAR activation per se induces HCCs carrying β-catenin mutations, it concurrently down-regulates the Wnt/β-catenin pathway in non-tumoral liver. They also indicate that the relationship between CAR and β-catenin may be profoundly different between normal and neoplastic hepatocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE113708 | GEO | 2018/04/27

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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High frequency of β-catenin mutations in mouse HCCs induced by a non-genotoxic CAR agonist

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