ADAM10参与侵袭性垂体腺瘤侵袭迁移行为的机制研究

ADAM10 is a factor which has effect on cell invasion and migration.ADAM10 is involved in many key pathways in cells via shedding a lot of important proteins and moleculars.In previous study, we revealed that ADAM10 is overexpression in invasive pituitary adenoma, especially in high-grade pituitary adenoma.Further we found that CaM is an inhibitor of ADAM10 in shedding CD44 and L1,when src kinase was played as a promotor.But the definite mechanism is not clear. In this project，we will explore the regulation of ADAM10 in cleaving its downstreaming moleculars CD44 and L1. Further we will analyze the key factor in this pathway and detect expression of solube fragment of CD44 and L1 in serum. Combined with the clinical data, we will measure the association between ADAM10 expression in pituitary adenoma and the clinical features.To provide a new marker for clinical diagnosis and treatments, in future clinical decisions, this study will be notably significant.

ADAM10是一类影响细胞的侵袭迁移的重要因子。通过裂解多种重要蛋白分子，ADAM10参与了多条细胞内关键调控通路，但其在侵袭性垂体瘤中具体作用仍知之甚少。课题组前期首次证实ADAM10在侵袭性垂体瘤中特别是在高级别垂体瘤中表达明显升高，并且进一步通过细胞水平验证了钙调蛋白的抑制及src激酶的激活调控ADAM10介导细胞粘附蛋白CD44、L1裂解，但具体机制仍有待于进一步研究。本项目拟在前期基础上，进一步并利用慢病毒RNA干扰、蛋白芯片、组织芯片、免疫共沉淀、免疫组化、RT-PCR等技术，深入阐明ADAM10在侵袭性垂体腺瘤中裂解下游蛋白的具体调控机制。进而分析通路关键因子以及血液中其底物裂解片段表达对侵袭性垂体腺瘤临床特征的指示意义。为临床提供肿瘤分级，评估预后、制定治疗方案的实验依据，具有显著的临床意义。

垂体腺瘤为颅脑外科的常见肿瘤之一，虽然为良性肿瘤，但部分肿瘤的侵袭性生长仍会对患者的生存质量产生严重影响。该项目在前期研究的基础上，继续深入探讨ADAM10与src相互作用从而发挥其剪切作用的具体机制，研究发现，ADAM10发挥其剪切作用于src的活化以及ADAM10胞质片段的完整密切相关，且其表达水平可以影响垂体腺瘤细胞的增殖，克隆形成以及迁移行为。同时我们发现skp2蛋白在垂体腺瘤特别是泌乳素腺瘤中的高表达，深入研究后发现skp2在泌乳素腺瘤中所介导的溴隐亭抵抗机制。在临床工作中，我们努力收集，随访病例，对垂体腺瘤卒中的临床，影像，分子学特点进行了总结，同时将分子研究结果与临床结合，探索血清中CD44剪切片段表达与ADAM10以及垂体腺瘤特点的相关性，以期为将来的诊治提供有效的分子指标。