Further evidence on the janus‐faced nature of the epidermal growth factor receptor: From liver regeneration to hepatocarcinogenesis

Abstract

Potential conflict of interest: Nothing to report. See Article on Page 604 After partial resection or parenchymal injury, the liver mounts a remarkable regenerative and self‐protective reaction. The mechanisms orchestrating this process have been the subject of intensive research for almost a century. Among the multiple mediators involved in liver regeneration after partial hepatectomy (PH), inflammatory cytokines and growth factors play a central role, promoting the synchronous entry into the cell cycle of the otherwise quiescent and differentiated hepatocytes.1 c‐Met and the epidermal growth factor (EGF) receptor (EGFR or ErbB1), both highly expressed in hepatocytes, are the two principal tyrosine kinase growth factor receptors (receptor tyrosine kinases; RTKs) involved in liver regeneration.1 Interestingly, their extensive crosstalk and funtional overlapping manifests in different cellular backgrounds, including hepatocytes.1 c‐Met is bound and activated by hepatocyte growth factor (HGF), which is induced after liver resection.1 However, besides EGF, several ligands activate EGFR in hepatocytes leading to DNA synthesis and cell survival4 (Fig. 1A). Interestingly, persistent activation of the inflammatory signals and growth factor pathways involved in liver regeneration, including c‐Met and the EGFR, is also believed to participate in hepatocarcinogenesis.4Figure 1: Role of EGFR in liver regeneration and hepatocarcinogenesis evaluated in ΔEGFR transgenic mice. (A) Left panel: EGFR/ErbB1 signaling in hepatocytes is triggered by EGFR ligands, including EGF, transforming growth factor alpha (TGFα), amphiregulin (AREG), epiregulin (EREG), and heparin‐binding EGF (HB‐EGF). Binding of EGFR results in receptor dimerization and activation of its tyrosine‐kinase domain (KD), inducing the activation of intracellular signaling pathways, such as MAPK and AKT, leading to cell proliferation and survival. Right panel: Transgenic ΔEGFR mice express a truncated EGFR devoid of its KD in hepatocytes. This mutant allows the binding of EGFR ligands through heterodimerization with WT EGFR, but blocks intracellular signaling behaving as a dominant‐negative effector. (B) Left panel: Liver regeneration after PH is delayed in ΔEGFR mice. Inhibition of EGFR activity results in enhanced TGF‐β signaling, leading to increased expression of cell‐cycle inhibitors, and in reduced lipogenic activity. Up‐regulation of Hgf and urokinase‐type plasminogen activator (uPa), resulting in increased c‐MET signaling, partially compensate for lack of EGFR signaling. Right panel: ΔEGFR mice show delayed DEN‐induced hepatocarcinogenesis. Inhibited EGFR signaling is associated with reduced inflammation and enhanced expression of the purported tumor suppressor, Nox4. As observed in liver regeneration, Hgf expression is also up‐regulated.ΔEGFR mice initially develop less tumoral lesions than WTs, but at later stages, tumor burden is similar in both genotypes. Abbreviations: Ccl2, chemokine (C‐C motif) ligand 2; Cxcl1, chemokine (C‐X‐C motif) ligand 1; Fasn, fatty acid synthase; G6pdh, glucose‐6‐phosphate dehydrogenase, Tnf; tumor necrosis factor.The contribution of EGFR to liver regeneration has been addressed using different experimental approaches. Given that early studies showed that EGFR‐null mice were not viable,4 alternative strategies to elucidate EGFR function in the adult animal were needed. Mice with hepatocyte‐specific perinatal deletion of EGFR were generated and after PH delayed cell‐cycle progression, reduced hepatocellular proliferation and increased mortality were appreciated.6 Interestingly, these mice were more susceptible to acute liver injury induced by the carcinogen, diethylnitrosamine (DEN).7 Partially agreeing with these findings, a recent study also using hepatocyte‐specific EGFR‐null mice found delayed cell‐cycle progression and DNA synthesis after PH, but not increased CCl4‐mediated acute liver injury.3 However, codeletion of EGFR and c‐Met in hepatocytes markedly exacerbated CCl4‐induced damage, further supporting the cooperation between these two receptors.3 Other investigators employed EGFR‐targeted RNA interference to examine the involvement of EGFR in rat liver regeneration after PH.2 Consistent with the phenotype of hepatocyte‐specific EGFR‐null mice, EGFR knockdown reduced hepatocellular proliferation and a potentially compensatory up‐regulation of c‐Met was also observed.2 Albeit altogether, these observations supported the implication of EGFR in the early phases of liver regeneration, many unsolved questions remained, including the cellular mechanisms triggered by EGFR that might regulate hepatocellular proliferation and survival in vivo. Moreover, all these studies relied on EGFR elimination or down‐regulation and lack of EGFR in hepatocytes might promote adaptive mechanisms, complicating the interpretation of results. With these issues in mind, López‐Luque et al. developed an elegant transgenic mouse model in which E