A FUNCTIONAL STUDY OF UBIQUITIN C-TERMINAL HYDROLASE L1 EXPRESSION IN B-LYMPHOMA

描述（由申请方提供）：已观察到泛素C末端水解酶L1（UCH L1）表达升高，并与许多人类恶性肿瘤（包括B细胞淋巴瘤）的预后不良相关。虽然这种去泛素化酶在肿瘤发生中的参与已被提出，但在很大程度上缺乏验证，并且UCH L1在癌细胞中的生理功能和调节仍然主要未知。 虽然泛素/蛋白酶体系统在细胞致癌转化中的作用已经很好地建立，但去泛素化酶（DUBs）在这一过程中的影响在很大程度上尚未探索。我们最近的研究表明，EB病毒依赖的B细胞转化诱导正常B淋巴细胞表达泛素C末端水解酶L1（UCH L1），其去泛素化活性参与致癌途径的激活。 我们建议研究UCH L1的表达和酶活性是否影响B淋巴瘤细胞系的基本细胞功能，如增殖，存活和迁移。了解这些功能输入将确定UCH L1作为细胞周期进展的新参与者和广泛基础治疗方法的潜在靶点。 公共卫生相关性：泛素系统与肿瘤细胞内多种信号通路的调控密切相关，近年来已成为肿瘤治疗的重要靶点。尽管一些蛋白酶体抑制剂通过诱导癌细胞凋亡可用于治疗多种恶性肿瘤，但靶向泛素系统的其他步骤，如特异性DUB，可能产生更有选择性的效果，因为泛素化和去泛素化复合物特异性结合潜在底物。我们的初步结果表明，UCH L1酶活性的小分子抑制剂抑制B淋巴瘤细胞的跨内皮迁移，因此可能对淋巴癌具有潜在的抗侵袭作用。该提案的目的是获得UCH L1在转化细胞中生理功能的实验数据，并潜在地验证去泛素化酶UCH L1作为诊断标志物和特定恶性肿瘤如非霍奇金斯和某些霍奇金斯淋巴瘤的抗癌治疗的新靶点。

DESCRIPTION (provided by applicant): Elevated expression of Ubiquitin C-terminal Hydrolase L1 (UCH L1) has been observed and associated with a poor prognosis in a number of human malignancies, including B-cell lymphomas. Although the involvement of this deubiquitinating enzyme in oncogenesis has thus been suggested, verification is largely lacking, and physiological functions and regulation of UCH L1 in cancer cells are still mainly unknown. While the role of the ubiquitin/ proteasome system in cell oncogenic transformation is well etablished, the impact of deubiquitinating enzymes (DUBs) in this process is largely unexplored. Our recent studies show that Epstein-Bar Virus-dependent transformation of B-cells induces expression of Ubiquitin C-terminal Hydrolase L1 (UCH L1) in normal B- lymphocytes, and its deubiqutinating activity is involved in activation of oncogenic pathways. We propose to investigate whether expression and enzymatic activity of UCH L1 affects basic cellular functions such as proliferation, survival and migration in B-lymphoma cell lines. Understanding of these functional inputs will identify UCH L1 as a new player in cell cycle progression and a potential target for a broadly based therapeutic approach. PUBLIC HEALTH RELEVANCE: Closely involved in regulation of numerous signaling pathways in tumor cells, the ubiquitin system in the last several years has become an attractive target for anti-cancer therapy. Although some proteasome inhibitors are useful in treatment of a variety of malignancies by inducing apoptosis in cancer cells, targeting of other steps of the ubiquitin system, such as specific DUBs, might produce more selective effects, since ubiquitinating and deubiquitinating complexes specifically bind to potential substrates. Our preliminary results indicate that a small-molecule inhibitor of UCH L1 enzymatic activity inhibits trans-endothelial migration of B-lymphoma cells and therefore might have a potential anti-invasive effect on lymphoid cancers. The goal of this proposal is to obtain experimental data on UCH L1 physiological functions in transformed cells and potentially to validate the deubiquitinating enzyme UCH L1 as a diagnostic marker and a novel target for anti-cancer therapy in specific malignancies such as non-Hodgkins and certain Hodgkins lymphomas.