CYLD/HSP70在凋亡素诱导胶质瘤细胞有丝分裂灾变中的作用与机制

Glioma is a highly malignant tumor, invasive growth, surgery is difficult to completely remove tumor tissues, while tumor cells to chemoradiotherapy has significant resistance, and thus a high recurrence rate. In recent years, mitotic catastrophe in tumor cells to overcome drug resistance and radiosensitization aspects has showed significant advantages. The latest research showed that apoptin can actuate mitotic catastrophe causing apoptosis,the checkpoint of Spindle and cell cycle is a key point of mitotic catastrophe,CYLD and HSP70 respectively regulate spindle and cell cycle, we found that apoptin can reduce HSP70 and increase CYLD. Known miR-19 inhibits CYLD transcription,thus, we proposed scientific hypotheses: apoptin by miR-19 / CYLD and HSP70 regulates the cell cycle to induce mitotic. The SH3 domain is the most important screening target of anti-glioma drug, according to the above mechanism, we modified the apoptin to make domains of SH3 exposed to N end and have it play a stronger antitumor effect. The purpose of this study is elucidating the apoptin induces mitotic catastrophe for new theory basis, to further study apoptin fragments of domain exposed SH3 for glioma treatment effect and its molecular mechanism. This study is expected to provide new ideas and theoretical basis for the development of anti-glioma new drugs.

胶质瘤是高度恶性肿瘤，呈侵袭性生长，手术难以彻底清除肿瘤组织，对放、化放疗具有明显的抵抗性，复发率高。近年来有丝分裂灾变在克服肿瘤细胞耐药和放射增敏方面优势明显。最新研究表明凋亡素可通过诱导有丝分裂灾变引起肿瘤细胞凋亡，纺锤体和细胞周期检测点是有丝分裂灾变的关键点，CYLD和HSP70则分别调控纺锤体和细胞周期，我们发现凋亡素可上调CYLD、下调HSP70。已知miR-19可抑制CYLD转录，由此我们提出科学假设：凋亡素通过miR-19/CYLD途径和HSP70调控细胞周期诱导有丝分裂灾变凋亡。SH3结构域是抗胶质瘤药物筛选的重要靶点，根据上述机制我们将凋亡素改构，使其SH3结合结构域暴露于N端，以期发挥更有效的抗肿瘤能力。本研究旨在阐明凋亡素诱发有丝分裂灾变新理论基础上，进一步研究SH3结合结构域暴露凋亡素片段对胶质瘤治疗作用及分子机制，为胶质瘤新药研究提供理论基础和新视角。

胶质瘤是高度恶性肿瘤，呈侵袭性生长，手术难以彻底清除肿瘤组织，对放、化放疗具有明显的抵抗性，复发率高。我们以SH3结构域为靶点，自主设计了凋亡素衍生肽，并在体内外进行了一系列抗肿瘤作用的相关研究。我们按照课题计划书开展了项目研究，结果显示：1)凋亡素衍生肽在细胞和动物水平抑制脑胶质瘤细胞的增殖、侵袭，诱导凋亡；凋亡素衍生肽对转移型原位胶质瘤具有明显抑制作用。2)凋亡素衍生肽通过下调 HSP70 特异诱导胶质瘤细胞凋亡(Oncotaget.2017)；凋亡素衍生肽通过PI3K/Akt途径抑制胶质瘤细胞侵袭、迁移(Tumor Bio.2016)；3)AAV介导的凋亡素衍生肽抗肿瘤研究(BBRC.2017) ;4)凋亡素衍生肽通过PI3K/Akt途径诱导顺铂耐药胃癌细胞凋亡（Cancer Med.2018; J Cell Biochem.2018；5）相关研究申请了2项国家发明专利（CN104926943A ，CN1035 54266B）。