Skp2参与泌乳素腺瘤抵抗溴隐亭诱导凋亡的机制研究

Bromocriptine is the first-line drug for clinical prolactinoma treatment.It often controls the symptoms but not cure.Recurrence of hyperprolctinemia and increase of tumor volume are risk to patients who withdraw bromocriptine after treatment.It is a problem necessary to be tackled that how to overcome the resistance of apoptosis induced by bromocriptine and to enforce the effect of bromocriptine to prolactinoma.In our previous study, we found that expression of skp2 inhibit activity of downstream molecular of p53 pathway in duced by bromocriptine. Then we fisrt reveal bromocriptine inhibit ubiquitination of skp2 then elevate the level of skp2 protein in prolactinoma.We suggest that bromocriptine may have a bidirectional regulation of apoptosis via skp2 in prolactinoma.In this project, we will further clarify the mechanism of Pi3k/Akt/skp2 pathway in resistance to apoptosis induced by bromocriptine in prolactinoma.Then take advantage of our clinical case and tissue data, we analyse the association between skp2 pathway and the hyperprolactinemia symptom,invasiveness of tumor and recurrence of drug withdraw for further choose treatment program and target therapy.

目前溴隐亭为我国治疗泌乳素腺瘤的临床一线用药，但其对症状仅是控制而非治愈，如何克服肿瘤对溴隐亭诱导凋亡的抵抗，增强溴隐亭疗效仍是亟待解决的问题。课题组在前期实验中发现skp2 表达可以抑制泌乳素腺瘤中溴隐亭所介导的p53凋亡通路下游反应元件表达，进一步深入发现溴隐亭可以通过抑制skp2泛素化降解提高泌乳素腺瘤中的skp2蛋白水平，我们认为，溴隐亭很可能通过skp2介导了对泌乳素腺瘤细胞凋亡的双向调控。本项目拟在前期基础上，进一步利用RNA干扰及过表达技术、组织芯片、免疫共沉淀、免疫组化、RT-PCR等技术，深入阐明Pi3k/Akt/skp2通路介导泌乳素腺瘤抵抗溴隐亭诱导凋亡的通路机制，并结合临床资料分析skp2通路激活程度与肿瘤生物学特征以及溴隐亭敏感性等的相关性，为临床制定治疗方案以及可能的靶向治疗提供实验依据，具有显著的临床意义。

本项目拟在前期研究基础上深入阐明skp2下游分子通路介导泌乳素腺瘤抵抗溴隐亭诱导凋亡的机制。首先，研究发现了溴隐亭通过减少skp2与CDH1的结合而抑制了skp2的降解，联合skp2抑制剂和溴隐亭处理细胞，可以增加细胞凋亡。为溴隐亭耐药的泌乳素腺瘤治疗提供了skp2这一新颖靶向治疗靶点。其次，我们探索了ADAM10和src的互作机制，发现src的活性可影响其与ADAM10的胞浆段（693-748）发生结合，并调节其剪切底物的活性，该过程与CALM1相拮抗，联合ADAM10和src一直可以有效抑制垂体瘤的侵袭迁移，为侵袭性垂体瘤的靶向治疗提供了新的靶点选择。再次，探索发现SIRT1在侵袭性垂体瘤中，通过影响下游分子PTTG1从而调控细胞的增殖侵袭行为。最后，我们在临床资料研究中，发现伴高泌乳素血症的无功能腺瘤患者的临床特点，提出这类患者早期手术可能获得更好的内分泌功能恢复的关键，为垂体瘤临床治疗提供指导。