TCPOBOP-Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling.
TCPOBOP-Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling.
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DOI：
10.1002/hep.30109
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发表时间：
2019-04
期刊：
影响因子：
--
通讯作者：
Michalopoulos GK
中科院分区：
文献类型：
--
作者：
Bhushan B;Stoops JW;Mars WM;Orr A;Bowen WC;Paranjpe S;Michalopoulos GK
TCPOBOP（1，4-双[2-（3，5-二氯吡啶氧基）]苯）是一种组成型雄甾烷受体（CAR）激动剂，可诱导肝细胞增殖和肝肿大，而无任何肝损伤或组织损失。TCPOBOP诱导的直接增生被认为是CAR依赖性的，没有证据表明涉及细胞因子或生长因子信号传导。受体酪氨酸激酶（RTK），MET和EGFR，已知在部分肝切除术后的肝再生中发挥关键作用，但它们在TCPOBOP诱导的直接增生中的作用，尚未探讨，在本研究中进行了研究。使用MET KO小鼠沿着Canertinib治疗EGFR抑制，实现RTK介导的信号传导中断。MET和EGFR信号传导的联合消除[MET KO + EGFRi]，而不是单独的破坏，显著降低了TCPOBOP诱导的肝肿大和肝细胞增殖。TCPOBOP驱动的CAR活化在[MET KO + EGFRi]小鼠中没有改变，如通过核CAR易位和典型CAR靶基因的分析所测量的。然而，TCPOBOP诱导的细胞周期活化在[MET KO + EGFRi]小鼠中受损，这是由于调节细胞周期起始和进展的细胞周期蛋白的诱导缺陷。在[MET KO + EGFRi]小鼠中，TCPOBOP驱动的FOXM 1诱导作用大大减弱，FOXM 1是TCPOBOP介导的肝细胞增殖期间细胞周期进程的关键转录调节因子。有趣的是，TCPOBOP治疗导致HNF 4 α表达的短暂下降伴随着增殖反应;这在[MET KO + EGFRi]小鼠中未观察到。转录组学分析显示，绝大多数（~40%）主要与增殖反应相关但与药物代谢无关的TCPOBOP依赖性基因在[MET KO + EGFRi]小鼠中差异表达。总之，EGFR和MET信号传导的组合破坏导致TCPOBOP诱导的增殖反应的显著损害，而不改变CAR活化。
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. Taken together, combined disruption of EGFR and MET signaling lead to dramatic impairment of TCPOBOP-induced proliferative response without altering CAR activation.
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