Context-specific role of FGF21 in chronic liver diseases and hepatocarcinogenesis.

点击翻译按钮获取中文摘要

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Although most liver diseases leading to HCC can be treated and the HCC preventive effect of e.g. HBV vaccination or HCV therapy has been shown, the incidence of HCC continues to increase in most countries world-wide. Clinically, HCC represents a major challenge, and overall the incidence rate continues to be close to the mortality rate. In the long term, a better understanding of the molecular mechanisms of tumorigenesis will make it possible not only to closely monitor high-risk patients, but also to prevent or at least delay tumor development through chemopreventive approaches. The aim of this proposal is to investigate the role of fibroblast growth factor 21 in chronic liver diseases and hepatocarcinogenesis. Overall, the data published so far show an important role of FGF21 both in metabolic regulation and as an acute phase protein after tissue damage. With respect to its importance for HCC, a protective role in metabolic (NAFLD/ NASH) induced tumorigenesis has been demonstrated. On the other hand, however, a number of studies have shown that a sustained anti-oxidative stress response is also associated with accelerated carcinogenesis and elevated FGF21 levels have been identified as a prognostically negative biomarker in HCC. These contrasting observations are consistent with other redox-sensitive transcription factors such as NRF2 and CAR and underline the important context-dependent role of the stress response in chronic diseases and carcinogenesis. In the presented proposal the role of FGF21 will be evaluated in chronic liver damage and tumorigenesis in non-metabolic HCC models as well as in established HCC. This will be done in particular with regard to the clinical question whether FGF21 can be a molecular target for chemopreventive approaches in patients at risk or whether risks with potentially accelerated tumor development outweigh in the context of chronic liver injury. Since a clinical use of recombinant FGF21 is already being tested in clinical trials, this question is of direct clinical relevance.