HMGB1在白血病细胞凋亡和自噬调控机制的研究

The cross-regulation between antuohagy and apoptosis is still a hot spot in the field of life science.Recently，oue project team reported a novel pro-autophagy protein HMGB1 participating in tumor drug resistance published in a prestigous journal《Leukemia》.According to the close relationship between apoptosis and autophagy and that HMGB1 negatively regulates apoptosis of leukemia cells, the applicant puts forawrd the hypothesis that HMGB1 involved in regulating the autophagy and apoptosis in leukemia cells. In view of the above hypothesis, the project intends to explore a variety of advanced means and from several aspects to further discuss how HMGB1 is to regulate apoptosis and autophagy in two different autophagic models(classic starved and chemotherapy-induced models),of which the priority is whether HMGB1 influences the shear of autophagic key protein through Bcl-2 or other apoptosis pathways. This project is expected to reveal a new mechanism of HMGB1 in the regulation of apoptosis and autophagy, to expand a new field in the function of HMGB1,to provied new experimental clues in exploring the relationship between apoptosis and autophagy, and to supply new sights into the therapeutic interventions in leukemia.

细胞凋亡和自噬机制的探讨是生命科学的研究热点。最近项目组在著名期刊《Leukemia》上报道HMGB1作为一种新型的促自噬蛋白参与了肿瘤耐药。根据最新发现凋亡与自噬密切相关，以及HMGB1负性调节白血病细胞凋亡的事实，申请者提出HMGB1参与调控白血病细胞凋亡和自噬的假说。针对上述假说，本项目拟采用各种先进的手段，在二种不同的自噬模型中（饥饿经典基础模型和化疗药物诱导的经典模型），从多个方面进一步深入系统的探讨HMGB1是如何调控凋亡和自噬的发生。其中，HMGB1是否通过Bcl-2或者其它凋亡途径影响自噬关键蛋白的剪切是研究重点。开展本项目可望揭示HMGB1在白血病细胞凋亡和自噬中的新机制，为HMGB1的功能研究开辟新的领域，为探求凋亡和自噬的关系提供新的实验线索，为临床白血病的防治提供新的思路。

寻找肿瘤细胞耐药机制仍是一项严峻挑战。凋亡是一种程序性细胞死亡，自噬是一种程序性细胞存活途径，两者均为进化过程中保守的过程，它们之间的平衡和转换影响抗肿瘤药物的敏感性以及细胞的存活。大多数情况下，凋亡缺陷和自噬上调促进化疗耐药。本项目采用基因转染、WESTERN BLOT、免疫荧光、电镜等多种方法，探讨HMGB1在调控白血病细胞耐药及凋亡和自噬相互关系，结果发现Nrf2/HO-1信号通路参与了HMGB1诱导的K562/A02化疗耐药，HMGB1可能通过AMPK/m-TOR信号通路，增强细胞自噬，进而促进化疗耐药性。减少HMGB1的表达将有望成为减少肿瘤细胞化疗耐药性的一个新靶点。并且发现，PARP1-HMGB1信号途径介导的自噬抑制了TNFSF10介导的细胞死亡，HMGB1移位在TNFSF10耐药机制中起着至关重要的作用，抑制PARP1-HMGB1途径减少自噬但凋亡上调，为自噬和凋亡之间的联系提供分子学依据。