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

FGF21 在慢性肝病和肝癌发生中的特定作用。

• 批准号: 445875685
• 负责人: Professor Dr. Arndt Vogel
• 金额: --
• 依托单位: Klinik für Gastroenterologie, Hepatologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/445875685?language=en
• 关键词: Context; specific; role; FGF21; chronic

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.

肝细胞癌（HCC）是世界范围内第五大常见癌症，也是癌症相关死亡的第二大原因。虽然大多数导致HCC的肝脏疾病可以治疗，并且已经显示了例如HBV疫苗接种或HCV治疗的HCC预防效果，但HCC的发病率在世界上大多数国家继续增加。在临床上，HCC是一个主要的挑战，总体发病率仍然接近死亡率。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迟肿瘤的发展。本研究的目的是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，迄今为止发表的数据显示了FGF 21在代谢调节和组织损伤后作为急性期蛋白的重要作用。关于其对HCC的重要性，已经证明了其在代谢（NAFLD/ NASH）诱导的肿瘤发生中的保护作用。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，并且升高的FGF 21水平已被鉴定为HCC中的病理学阴性生物标志物。这些对比观察结果与其他氧化还原敏感性转录因子如NRF 2和CAR一致，并强调了应激反应在慢性疾病和致癌作用中的重要背景依赖性作用。在所提出的建议中，FGF 21的作用将在非代谢性HCC模型以及已建立的HCC中的慢性肝损伤和肿瘤发生中进行评估。这将特别针对以下临床问题进行：FGF 21是否可以成为处于风险中的患者的化学预防方法的分子靶标，或者潜在加速肿瘤发展的风险是否超过慢性肝损伤的风险。由于重组FGF 21的临床应用已经在临床试验中进行了测试，因此该问题具有直接的临床相关性。