Nuevo papel de la anfirregulina en la regeneracion hepatica y en el desarrollo del hepatoccarcinoma

Abstract

Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors, such as the epidermal growth factor receptor (egfr) system. Amphiregulin (AR) is a ligand of the egfr, whose expression is not detected in healthy liver. We have investigated the role of AR in liver regeneration, damage, and hepatocarcinogenesis. Ar expression is detected in chronically injured liver and is rapi dl y induced after partial hepatectomy in rodents, where ar behaves as a primary mitogen for the hepatocytes, through the egfr. Consistently, ar-null mice displayed impaired proliferative responses after partial hepatectomy Ar expression is up-regulated in Fas-induced acute liver damage and its administration abrogated liver injury and showed anti-apoptotic effects in hepatocytes. Ar null mice showed signs of chronic liver damage and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. Ar is also expressed in human hepatocellular carcinoma tissues and it is involved in the acquisition and maintenance of neoplastic traits in the liver. Altogether, our findings indicate that ar is an early-response growth factor that contributes to the initial phases of liver regeneration by promoting growth and survival signals to the hepatocytes and thus it may be therapeutic in liver diseases, such as acute liver failure. However, the sustained expression of ar can contribute to hepatocarcinogenesis.