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

肝细胞癌（HCC）是全球第五大常见癌症，也是癌症相关死亡的第二大原因。虽然大多数导致HCC的肝脏疾病都可以治疗，并且HBV疫苗接种或HCV治疗等预防HCC的效果已得到证实，但HCC的发病率在世界上大多数国家仍在继续增加。在临床上，HCC是一个重大挑战，总体发病率继续接近死亡率。从长远来看，更好地了解肿瘤发生的分子机制不仅可以密切监测高危患者，还可以通过化学预防方法预防或至少延缓肿瘤的发展。本研究旨在探讨成纤维细胞生长因子21在慢性肝病和肝癌发生中的作用。总的来说，到目前为止发表的数据表明FGF21在代谢调节和组织损伤后急性期蛋白中都起着重要作用。关于其在HCC中的重要性，已证实其在代谢（NAFLD/ NASH）诱导的肿瘤发生中具有保护作用。然而，另一方面，许多研究表明，持续的抗氧化应激反应也与加速的癌变有关，并且FGF21水平升高已被确定为HCC预后阴性的生物标志物。这些对比结果与其他氧化还原敏感转录因子（如NRF2和CAR）一致，并强调了应激反应在慢性疾病和癌变中的重要环境依赖性作用。在提出的建议中，FGF21将在非代谢性HCC模型和已建立的HCC中评估慢性肝损伤和肿瘤发生中的作用。这将特别涉及临床问题，即FGF21是否可以作为有风险患者的化学预防方法的分子靶点，或者在慢性肝损伤的背景下，潜在加速肿瘤发展的风险是否大于风险。由于重组FGF21的临床应用已经在临床试验中进行了测试，因此这个问题具有直接的临床相关性。

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.