Gender-Specific Interplay of Signaling through β-Catenin and CAR in the Regulation of Xenobiotic-Induced Hepatocyte Proliferation

Abstract

Aberrant signaling through the Wnt/β-catenin pathway is a critical determinant in human and rodent liver carcinogenesis and generally accepted to be a potent driver of proliferation. Xenobiotic agonists of the constitutive androstane receptor (CAR) induce massive acute hyperplasia of mouse liver and facilitate the outgrowth of hepatocellular carcinomas with activated β-catenin. In the present study, the interplay of β-catenin-dependent and CAR-dependent signaling in the liver and its effect on hepatocyte proliferation were analyzed in transgenic mice with hepatocyte-specific knockout of Ctnnb1 (encoding β-catenin) following treatment with two CAR agonists, 1,4-bis[2-(3,5-dichloropyridyloxy)]-benzene (TCPOBOP) and phenobarbital. Hepatocyte-specific knockout of β-catenin inhibited CAR agonists-induced hepatocyte proliferation in male mice. By contrast, the proliferative effect of CAR agonists was strongly augmented in female β-catenin knockout animals. This was due to prolonged proliferation of the knockout hepatocytes. CAR-mediated hepatocyte proliferation was, at least in part, dependent on estrogen signaling and was associated with enhanced expression of FoxM1 and elevated activity of the PDK1/p90RSK pathway. In conclusion, our study shows that gender-specific factors determine whether β-catenin signaling plays a pro- or an antiproliferative role in the regulation of mouse hepatocyte proliferation induced by CAR agonists.

TCPOBOP‐Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling

“…Our previous data and several other reports indicated that both MET and EGFR can regulate an important transcription factor, FOXM1, which governs transcription of genes important for DNA replication and mitosis . FOXM1 is considered to be critical for inducing TCPOBOP‐mediated hepatocyte proliferation . Consistent with these previous reports, FOXM1 was remarkably induced by TCPOBOP at all of the time points in control mice with peak induction (10‐fold) coinciding with the time point of peak proliferation (day 2) (Fig.…”

“…A). β‐catenin signaling is another pathway regulated by MET and reported to be involved in TCPOBOP‐induced proliferation that was not altered in our model (Supporting Fig. B).…”

“…This differential attenuation of proliferation was attributed to decrease in YAP activity, which appeared not to be altered in our model. An inverse effect was observed in female β‐catenin KO and Gadd45β KO mice, which displayed a lower level of drug metabolic enzymes but increased proliferative response to TCPOBOP treatment …”

“…It regulates transcription of cyclins (such as cyclin B1), Cdc25 phosphatases (that activate cyclin‐dependent kinases), several mitotic regulators (such as polo like kinase 1, aurora B kinase, and survivin), and negatively regulates the expression of cell cycle inhibitors such as p27. FOXM1 is considered a critical mediator of TCBOBOP‐induced proliferative response . FOXM1 was reported to be required for improved regenerative response triggered by TCPOBOP treatment in an extensive liver resection (86%) model and also important for maintaining TCPOBOP‐induced proliferative response in aged mice .…”

Complete response of Ctnnb1-mutated tumours to β-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model

“…DEN at high doses in 6-week-old male leads to DNA damage and adducts possibly through oxidative stress, which may lead to mutations in CTNNB1 along with others [28]. Since Constitutive Androstane Receptor (CAR), a nuclear orphan receptor, was recently identified as a β-catenin target [16], it is likely that introduction of PB, which is a CAR agonist, provides growth advantage to hepatocytes with activating β-catenin gene mutations [3, 17]. Thus tumor nodules in DEN/PB model are predominantly β-catenin mutated.…”