Dissecting the Role of Epidermal Growth Factor Receptor Catalytic Activity During Liver Regeneration and Hepatocarcinogenesis
Dissecting the Role of Epidermal Growth Factor Receptor Catalytic Activity During Liver Regeneration and Hepatocarcinogenesis
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DOI：
10.1002/hep.28134
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发表时间：
2016-02-01
期刊：
影响因子：
13.5
通讯作者：
Fabregat, Isabel
中科院分区：
文献类型：
--
作者：
Lopez-Luque, Judit;Caballero-Diaz, Daniel;Fabregat, Isabel
不同的数据支持表皮生长因子受体（EGFR）途径在肝再生和肝癌发生过程中的作用。然而，一些重要的问题，例如协调其行动的确切机制以及独特的职能和多余的职能，尚未得到充分界定。在这里，我们提出了一种新的转基因小鼠模型表达肝细胞特异性截断形式的人EGFR，作为负显性突变体（德尔塔EGFR），并允许定义其酪氨酸激酶依赖性功能。结果表明，在肝再生的早期阶段，EGFR催化活性的关键作用。因此，在三分之二部分肝切除术后，DEGFR肝脏显示出较低和延迟的增殖和较低的增殖信号激活，这与转化生长因子β途径的过度激活相关。改变的再生反应与转化生长因子-β通过诱导细胞周期负调控因子的细胞生长抑制作用的放大有关。有趣的是，部分肝切除术后Delta EGFR肝脏中的脂质合成受到严重抑制，揭示了EGFR激酶活性作为再生肝细胞中脂质代谢调节剂的新功能。尽管有这些深刻的变化，Delta EGFR肝脏能够通过过度激活代偿信号（如c-Met）恢复肝脏质量。我们的研究结果还表明，EGFR的催化活性是至关重要的，在早期癌前阶段的肝脏，因为三角洲EGFR小鼠表现出延迟出现二乙基亚硝胺诱导的肿瘤，这与减少增殖和延迟二乙基亚硝胺诱导的炎症过程。结论：这些研究表明，EGFR催化活性在肝再生和癌变的初始阶段是至关重要的，并为这种激酶如何调节肝脏病理生理学提供了关键的机制见解。
Different data support a role for the epidermal growth factor receptor (EGFR) pathway during liver regeneration and hepatocarcinogenesis. However, important issues, such as the precise mechanisms mediating its actions and the unique versus redundant functions, have not been fully defined. Here, we present a novel transgenic mouse model expressing a hepatocyte-specific truncated form of human EGFR, which acts as negative dominant mutant (Delta EGFR) and allows definition of its tyrosine kinase-dependent functions. Results indicate a critical role for EGFR catalytic activity during the early stages of liver regeneration. Thus, after two-thirds partial hepatectomy, DEGFR livers displayed lower and delayed proliferation and lower activation of proliferative signals, which correlated with overactivation of the transforming growth factor-beta pathway. Altered regenerative response was associated with amplification of cytostatic effects of transforming growth factor-beta through induction of cell cycle negative regulators. Interestingly, lipid synthesis was severely inhibited in Delta EGFR livers after partial hepatectomy, revealing a new function for EGFR kinase activity as a lipid metabolism regulator in regenerating hepatocytes. In spite of these profound alterations, Delta EGFR livers were able to recover liver mass by overactivating compensatory signals, such as c-Met. Our results also indicate that EGFR catalytic activity is critical in the early preneoplastic stages of the liver because Delta EGFR mice showed a delay in the appearance of diethyl-nitrosamine-induced tumors, which correlated with decreased proliferation and delay in the diethyl-nitrosamine-induced inflammatory process. Conclusion: These studies demonstrate that EGFR catalytic activity is critical during the initial phases of both liver regeneration and carcinogenesis and provide key mechanistic insights into how this kinase acts to regulate liver pathophysiology.