Role of MET and EGFR Signaling in Hepatomegaly and Hepatocyte Proliferation Induced by TCPOBOP (1,4‐Bis [2‐(3,5‐Dichloropyridyloxy)] Benzene) in Mice

Abstract

Growth factor receptors MET and EGFR are known to play a critical role in liver regeneration after partial hepatectomy. TCPOBOP (1,4‐Bis [2‐(3,5‐Dichloropyridyloxy)] benzene), a CAR agonist, induces robust hepatocyte proliferation and hepatomegaly without any injury or tissue loss. The underlying mechanisms are considered to be different compared to the mechanisms of liver regeneration after partial hepatectomy with no evidence of involvement of cytokine and receptor tyrosine kinase signaling. Role of signaling via growth factor receptors, MET and EGFR, in TCPOBOP‐induced direct hyperplasia is not yet investigated. Here we report that both MET and EGFR are rapidly activated after TCPOBOP treatment in mice preceding any substantial increase in hepatocyte proliferation and liver mass. This was accompanied by concomitant activation of downstream ERK1/2 and AKT signaling pathways. Systemic elimination of MET (MET KO) in mice resulted in a moderate decrease in TCPOBOP‐induced hepatomegaly. However, treatment with Canertinib, an EGFR inhibitor (EGFRi), did not significantly alter TCPOBOP‐induced liver growth. Interestingly, combined elimination of MET and EGFR signaling (MET KO + EGFRi‐treatment) dramatically reduced TCPOBOP‐induced hepatomegaly and remarkably attenuated hepatocyte proliferation. In conclusion, our study revealed a novel role of signaling via EGFR and MET receptors in hepatomegaly and hepatocyte proliferation induced by TCPOBOP.