The impact of Cyclin E1 in alcohol-induced organ disease and carcinogenesis within the Gut-liver axis

肠道和肝脏之间的相互作用受损是各种肝脏疾病的常见原因。肠上皮通透性的改变导致肠道菌群密集通过，随后发生肝脏炎症或终末期癌变。先前的研究表明，抑制细胞周期介质Cyclin E1对小鼠肝脏肿瘤发生模型具有保护作用。然而，Cyclin E1的缺失导致慢性酒精暴露后肝脏和肠道上皮损伤增加。本研究的主要目的是阐明Cyclin E1在酒精诱导的肠道和肝脏肿瘤发生中的作用。为此，我们将深入分析小鼠慢性酒精暴露后Cyclin E1完全耗尽的后果，并在肠-肝轴上识别效应细胞。此外，使用小鼠模型，将检验抑制Cyclin E1是否对酒精诱导的肝癌或结肠癌的发展具有保护作用。最后，我们将通过确定酒精性肝癌和结肠癌患者中Cyclin E紊乱的患病率来探索临床前研究的临床转化性。总之，这项研究非常有趣，因为它将能够揭示抑制Cyclin E1是否为治疗酒精相关癌症提供了一种新的治疗选择。

The impaired interaction between gut and liver is a frequent cause of various liver diseases. Alterations in the permeability of the intestinal epithelium lead to the intensive passage of intestinal microflora followed by hepatic inflammation or end-stage carcinogenesis. In previous work, it was shown that inhibition of the cell cycle mediator Cyclin E1 has a protective effect in an established mouse model of liver tumorigenesis. However, the absence of Cyclin E1 caused increased liver and gut epithelium injury after chronic alcohol exposure. The main aim of the current proposal is to elucidate the function of Cyclin E1 in the alcohol-induced tumorigenesis in the intestine and in the liver. To this end, an in-depth analysis of the consequences of complete Cyclin E1 depletion in mice after chronic alcohol exposure will be performed in the gut-liver axis, and effector cells will be identified. Additionally, using murine models, it will be examined whether inhibition of Cyclin E1 is protective against the development of alcohol-induced liver or colon cancer. Finally, the clinical translationality of our preclinical research will be explored by determining the prevalence of Cyclin E disorders in patients with alcohol-induced liver and colon cancer. In summary, this study is of utmost interest since it will be able to unveil whether the inhibition of Cyclin E1 provides a novel therapeutic option for the treatment of alcohol-related cancers.