SRSF3 degradation in liver disease and hepatocellular carcinoma

我们已经发表，消除肝细胞中特定的RNA剪接因子SRSF3会导致 慢性肝损伤，糖脂代谢紊乱，炎症，纤维化，最终肝脏 癌症。因此，剪接因子的缺失不会导致肿瘤，而是会导致癌症的易感性， 类似于肿瘤抑制基因。我们已经证明SRSF3的丢失在早期肝病中被发现 人类和小鼠，除了我们之前展示的在肝癌中迷失之外。而当 脂肪性肝病发展为脂肪性肝炎和肝硬变过程中的病理变化 已经有了很好的记录，我们仍然不知道为什么有些人可以保持相对良性的脂肪肝 而其他人则进步到更多地服务于肝病，包括肝硬变和癌症。 基于大量的初步数据，我们发现SRSF3蛋白的半衰期很短，而且它的 水平受蛋白酶体降解的影响很大。这不是通常的泛素介导的途径，但 相反，这是一种新的途径，涉及与NEDD8蛋白的结合，以响应脂质诱导的压力。我们 相信SRSF3可能是决定肝病进展或稳定的把关人。一个 个体对进展的敏感性取决于SRSF3对应激诱导的敏感性 退化。因此，我们提议进行一系列全面的实验，以了解SRSF3是如何 对应激反应的降解以及稳定SRSF3并防止其降解是否可以阻止 进展为NASH、肝硬变和肝癌。这些研究将解决有关以下方面的关键问题 蛋白质动态平衡与致癌的基本生物学过程，将生化、细胞 以及对肝脏中缺乏特定剪接因子的小鼠进行生理学研究的分子生物学实验。 我们将确定靶向SRSF3的E3-连接酶复合体的成分， 导致SRSF3破坏的途径，以及SRSF3结合和去共轭的平衡是如何 维护好了。我们研究了在小鼠体内表达耐降解的SRSF3或阻断代谢 将防止早期肝病发展为炎症、纤维化和肝硬变，我们将确定 无论这种方法是预防肝癌还是可以用来逆转小鼠的肝癌。

We have published that eliminating a particular RNA splicing factor SRSF3 in hepatocytes causes chronic liver damage, disruptions in glucose and lipid metabolism, inflammation, fibrosis, and eventually liver cancer. So the loss of the splicing factor does not cause tumors but rather creates a pre-disposition to cancer, similar to a tumor suppressor gene. We have since shown that loss of SRSF3 is found in early liver disease in both humans and mice, in addition to being lost in liver cancer which we had shown previously. While the pathological changes that occur during the progression of fatty liver disease to steatohepatitis and cirrhosis have been well documented, we still do not know why some people can maintain relatively benign fatty livers while others progress to more serve liver disease including liver cirrhosis and cancer. Based on extensive preliminary data, we have found that the SRSF3 protein has a short half-life and its levels are acutely regulated by proteosomal degradation. This is not the usual ubiquitin mediated pathway but rather a novel pathway involving conjugation to the NEDD8 protein in response to lipid-induced stress. We believe that SRSF3 may be the gatekeeper that determines whether liver disease progresses or is stable. An individual’s susceptibility to progression is determined by the susceptibility of SRSF3 to stress-induced degradation. So we are proposing a comprehensive series of experiments to understand how SRSF3 is degraded in response to stress and whether stabilizing SRSF3 and preventing its degradation can halt the progression to NASH, cirrhosis and liver cancer. These studies will address key questions concerning the fundamental biological process of protein homeostasis and carcinogenesis and will integrate biochemical, cell and molecular biological experiments with physiological studies in mice lacking specific splicing factors in liver. We will determine the components of the E3-ligase complex that targets SRSF3 for neddylation, the pathway leading to destruction of SRSF3, and how the balance of SRSF3 conjugation and deconjugation is maintained. We investigate whether expressing a degradation-resistant SRSF3 or blocking neddylation in mice will prevent the progression of early liver disease to inflammation, fibrosis and cirrhosis, and we will determine whether this approach prevents liver cancer or can be used to reverse liver cancer in mice.