FAT10调控HOXB9在原发性肝癌侵袭转移中的作用及机制研究

Invasion and metastasis is the main reason for poor prognosis in patients with primary hepatocellular carcinoma(PHC). Studies have revealed that the ubiquitin-like protein FAT10 played an important role in PHC development. Overexpression of HOXB9 was closely related to tumor invasion and metastasis. However, the association between them and their role in the invasion and metastasis of PHC remains unclear. Our previous studies found that the reduction of FAT10 protein could cause HOXB9 decreased expression in PHC cells by cDNA microarray and Western blot. FAT10 protein and HOXB9 protein were both overexpressed in PHC tissues. Thus, we presumed that FAT10 could affect PHC invasion and metastasis through regulating HOXB9. To further identify the invasion and metastasis effect of FAT10 regulating HOXB9 in PHC cells and explore the mechanism of FAT10 regulating HOXB9, we will firstly investigate the impact on the biological activity of FAT10 regulating HOXB9 on PHC invasion and metastasis in vivo and vitro. Then to observe the molecular biology mechanism of FAT10 regulating HOXB9. Finally, we detect the protein expression of FAT10 and HOXB9 in clinical PHC samples and analyze the relationship with clinicopathological and prognosis.Accordingly, this study will supply the theoretical basis for clarifying mechanism of PHC invasion and metastasis.

侵袭和转移是影响原发性肝癌患者预后不良的主要原因。研究已证明类泛素蛋白FAT10在肝癌发生发展中起重要作用；HOXB9过表达与肿瘤侵袭和转移密切相关。然而两者间关系及它们在原发性肝癌侵袭和转移中的作用仍不清楚。我们前期通过基因芯片筛选及Western blot等实验证实在肝癌细胞中降低FAT10表达可导致HOXB9表达下降；肝癌组织中FAT10及HOXB9蛋白均呈过表达。因此我们推测FAT10通过调控HOXB9表达而影响肝癌的侵袭和转移。为证实FAT10调控HOXB9在肝癌发生侵袭和转移中的生物学特性作用并探讨其作用机制，本课题拟先通过体外和体内研究明确FAT10调控HOXB9表达对肝癌发生侵袭和转移的生物学特性影响；再探讨FAT10调控HOXB9分子生物学机制；并分析FAT10和HOXB9蛋白在肝癌组织中表达与临床病理及预后的关联；本研究将为阐明原发性肝癌发生侵袭和转移机制提供理论依据。

类泛素蛋白FAT10和HOXB9能够分别促进肝细胞癌（HCC）侵袭转移。在本研究中，我们分析了FAT10和HOXB9在肝癌中的临床病理意义，并研究了FAT10在HOXB9介导的侵袭和转移中的关键作用。FAT10与HOXB9在肝癌组织中表达明显高于癌旁组织，而两者表达的关系呈正相关，并且发现与肿瘤恶性特征相关。RNAi沉默FAT10的表达能够降低HOXB 9的表达并抑制体外和体内肝细胞癌的侵袭和转移。FAT10的干扰效应能够被HOXB9的过表达所逆转，然而RNAi沉默HOXB9表达能够抑制由FAT10驱动的肝癌侵袭转移。总而言之，FAT10直接结合β-catenin并且抑制它的泛素化和降解，从而通过β-catenin /TCF4信号通路调控HOXB9的表达。我们的结果揭示了一个新的肝癌的FAT10-β-catenin／TCF4- HOXB9调控通路机制，其功能失调能够驱动肝癌的侵袭和转移。