Abstract
The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC) highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs).
Highlights
The epidermal growth factor receptor (EGFR, known as ErbB1 or HER-1) is a transmembrane receptor that belongs to the family of receptor tyrosine kinases (RTK) [1]
In EGFR-deficient livers, regeneration was impaired after 2/3 hepatectomy showing reduced cyclin D1 expression and impaired G1-S phase entry, demonstrating that EGFR is a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration [35] (Figure 1a)
No mortality and delay of liver regeneration was observed in EGFR-silenced rats after partial hepatectomy, shEGFR treatment suppressed mitosis and proliferation. Limitations of this system comprise the fact that EGFR messenger RNA and protein were not completely absent [64]. These results consistently demonstrate that EGFR is a critical regulator of hepatocyte proliferation in the initial phases of liver regeneration (Figure 1a)
Summary
Several groups generated knockout mice deficient of EGFR and its ligands [24]. AR, BTC, EGF, EREG and EPGN knockout mice did not show any overt phenotype or histological abnormalities [25,26,27,28], beside a mild mammary gland phenotype observed in virgin AR knockout mice [25]. Further studies from our laboratory using conditional knockout mice revealed that perinatal deletion of EGFR in hepatocytes alone with the transgenic Alfp-Cre line resulted in reduced body size and weight, which became apparent from the third postnatal week onwards [35]. Absence of the EGFR protein in the liver of these mice occurred only 3–4 weeks after induction of recombination, providing a possible explanation for the different phenotype compared to Alfp-Cre-mediated deletion [35]. These results suggest that EGFR and its ligands are not crucial for embryonic liver development
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