REGγ在肝癌及肝癌骨转移发生发展中的调控作用与机制研究

Hepatocellular Carcinoma is an aggressive liver tumor. Bone metastasis of HCC possess a high incidence, and often result in serious impair to patient health. Until now, the mechanism remains unclear, and there is no specific molecular target for therapy. REGγ, a proteasome activator, was reported to be involved in regulating tumor-related genes of liver cancer cells. Here we showed that the expression of REGγ was increased in the liver cancer for 74.18% patients according to the bioinformatics analysis, and microarray data indicated that the level of REGγ was higher in late stage patients than that of the early stage patients. In addition, the expression of REGγ was increased in the samples of liver cancer or bone metastasis of liver cancer. Next, we generated the transgenic animal model of liver cancer and found the volume of tumors in REGγ knockout mice was markedly reduced in comparison with that in REGγ WT mice. At the same time, we succeeded in generating the in situ bone mouse model and found the bone was damaged when REGγ was normal. Besides, we showed that the cell migration was inhibited and the level of smurf2 was increased when the REGγ’s expression was repressed in liver cancer cells. However, the expression of Smad3 and Zeb1 was decreased. The present project, based on the previous findings, intends to focus on the signaling pathway how REGγ regulates TGF-β signaling pathway with the help of hospital and then provide a novel potential method in the target therapy in liver cancer and bone metastasis of liver cancer.

肝细胞性癌（HCC）是一种侵袭性肝肿瘤，容易发生骨转移，严重危害患者健康。最近研究表明，蛋白酶体激活因子REGγ在肝癌细胞中参与调控肿瘤信号分子。课题组前期生物信息学分析发现74.18%肝癌病例呈现REGγ高表达，微阵列数据表明晚期肝癌病人REGγ水平高于早期肝癌病人的REGγ水平；REGγ在肝癌以及骨转移临床样本中高表达；建立肝癌原位动物模型，发现REGγ正常小鼠肿瘤数多于REGγ敲除小鼠肿瘤数；利用肝癌细胞系建立骨原位肿瘤模型，发现REGγ正常小鼠骨被破坏；肝癌细胞中低表达REGγ细胞迁移能力被限制，Smurf2表达增高，Smad3和Zeb1的水平减少。这些发现提示REGγ参与肝癌和肝癌骨转移过程。本项目拟在前期工作基础上，通过与医院合作，在临床、动物模型和细胞水平揭示 REGγ在肝癌发生发展中对TGF-β信号通路及其下游分子的调控机理，为临床治疗肝癌及肝癌骨转移提供新思路。

近年来，非泛素依赖的蛋白质降解成为正在兴起的研究领域，REGγ是其中代表性的蛋白酶体激活因子。蛋白酶体的上游信号如何通过修饰“蛋白酶体激活因子”来影响靶蛋白质降解的机制仍然不明确。另外，传统蛋白酶体抑制剂的脱靶毒性，限制了其在实体肿瘤治疗中的应用。课题组近5年聚焦REG-20S蛋白酶体的生物学功能及调控，重要研究成果有：1）明确REGγ在肿瘤发生和转移中的调控机理；2）筛选到调控REGγ-蛋白酶体功能的上游调节因子NIP30；3）利用新型纳米载体携载传统蛋白酶体治疗骨转移癌。这些研究明确了REGγ相关的泛素非依赖的蛋白质降解通路参与多种肿瘤的调控机理，多学科交叉，诠释基础研究的临床价值，最终为肿瘤的精准治疗提供参考。

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