| 抄録 |
Hepatocellular carcinoma（HCC）slowly unfolds on a background of chronic liver injury, fibrosis and inflammation. Interestingly, a number of key mechanisms that participate in the normal liver regenerative response are also involved in the carcinogenic process. These include inflammatory and growth factor-mediated circuits that become dysregulated as disease progresses. Among them is the epidermal growth factor receptor（EGFR）signalling system, which has been shown to participate both in liver regeneration and hepatocarcinogenesis. Given the complex nature of both processes, the development of crosstalks between different molecular pathways is likely to occur. Furthering our knowledge of these mechanisms will help to design effective therapies that could be useful both in regenerative medicine and HCC tretament. We identified a novel role for the EGFR ligand amphiregulin（AR）in liver disease progression. AR is not expressed in normal liver, but it is detected in experimental models of acute liver damage and regeneration, in patients with chronic liver injury, and in a significant proportion of human HCCs. AR expression is induced by inflammatory mediators, as well as by fibroblast growth factor 19（FGF19）, a recently identified HCC-promoting factor. AR participates in normal liver regeneration, but also stimulates the growth and survival of HCC cells, and their resistance to anti cancer drugs. We have uncovered new mechanisms involved in the pro-tumorigenic effects of AR, including the expression of oncogenic splice variants of the tumor suppressor protein p73, the upregulation of the Yap transcription co-activator and the inhibition of serpina3 expression. These observations suggest that AR could be an interesting target in anti-HCC strategies. On the other hand, we also found a crosstalk between AR and FGF19 that led us to identify important hepatoprotective and pro-regenerative effects of this latter growth factor with potential clinical applications. |
