白介素13在甲状腺乳头状癌发生中的作用与调控机制

Along with the increase of incidence rate of papillary thyroid carcinoma (PTC), the diagnostic and therapeutic tools that aimed directly at etiological factors were needed imperiously. Deubiquitinase plays an important role in the regulation of protein degradation, which involved in many types of cancer initiation and progress. Our previous studies have shown that express level of ubiquitin carboxyl-terminal hydrolase L5 (UCH-L5) and interleukin-13 (IL-13) were relatively higher in PTC than those in normal thyroid tissue. The interaction between UCH-L5 and IL-13 was also confirmed. UCH-L5 may mediate the protein level of IL-13 through deubiquitination. Based on our experimental results and previous reports in the literature, we hypothesized that overexpression of UCH-L5 could induce deubiquitination of the substrate protein IL-13 and increases its accumulation through their interaction. UCH-L5 then interacts with IL-13 to form a nuclear complex and accelerates IL-13 nuclear export to give rise to cell cycle disorders and abnormal cell proliferation, thus resulting to the development of PTC. This project will detect the levels of UCH-L5 and IL-13 in PTC, assess their clinical significance, validate the role of UCH-L5 and PTC in development of PTC and further clarify their interactions of UCH-L5 and IL-13 and the molecular mechanism of UCH-L5-induced IL-13 deubiquitination in tumorigenesis of PTC to provide a theoretical basis for PTC diagnosis and treatment.

甲状腺乳头状癌(PTC)是最常见的内分泌癌，其发病机制并不十分明了。我们前期研究表明泛素羧基末端水解酶L5(UCH-L5)和白介素13(IL-13)在PTC中过量表达，并证实UCH-L5与IL-13可能存在相互作用，UCH-L5正向调控IL-13蛋白含量。根据以往实验基础和相关文献报道，我们提出如下假说：UCH-L5通过与核内底物蛋白IL-13相互作用，导致IL-13去泛素化程度增加而聚积；IL-13与UCH-L5相互作用形成复合物出核，进而激活转录因子AP-1和STAT6，使下游癌蛋白增加，从而促进细胞增殖、抑制细胞凋亡，导致PTC发生发展。本项目拟探讨UCH-L5和IL-13在PTC中的表达及临床意义；验证UCH-L5和IL-13在PTC发生发展中的作用；明确UCH-L5和IL-13的相互作用，阐明UCH-L5和IL-13参与PTC发生发展的分子机制，为PTC的诊断和治疗提供理论依据。

甲状腺乳头状癌(PTC)是最常见的内分泌癌，其发病机制并不十分明了。我们的研究发现了IL-13在甲状腺乳头状癌中的表达高于良性结节。并且，IL-13蛋白在甲状腺滤泡亚型乳头状癌中高表达，在甲状腺柱状细胞亚型乳头状癌中弱阳性表达，而在结节性甲状腺肿组织中不表达。从而能为IL-13可以作为潜在有效的鉴别甲状腺结节良恶性的候选分子标记物提供可能。同时，我们深入研究IL-13和UCH-L5在甲状腺乳头状癌发生发展中的作用及其调控机制。探讨IL-13和UCH-L5在PTC中的表达及其临床意义，验证UCH-L5和IL-13在PTC发生发展中的作用，明确UCH-L5和IL-13之间的相互作用，阐明UCH-L5和IL-13参与PTC发生发展的可能分子机制；并且从免疫微环境角度发现甲状腺乳头状癌组织中的肿瘤相关巨噬细胞具有M2 型巨噬细胞特征，以进一步理解甲状腺乳头状癌发生发展的免疫机制，为PTC的诊断和治疗提供理论依据与实践基础。此外，进一步分析了IL-13在甲状腺乳头状癌中异常表达的根源；我们利用miRecords生物信息学预测工具，进一步预测分析了针对IL-13作为直接调控靶标的可能miRNAs分子，其可能的调控miRNA分子为let-7家族，计划在进一步的研究中分析其家族中具体亚型的探索。试图在后期研究阶段阐明了炎症微环境可能引起let-7家族异常表达，从而致使IL-13表达水平异常的根源，为后续进一步深入探索机制研究奠定了基础。