癌细胞衰老与促凋亡在抑制肝癌中的协同机制

Hepatocellular carcinoma (HCC) is a cancer with high morbidity and mobility, for which effective treatment is limited. Cellular senescence is a state of irreversible cell growth arrest. Senescent cancer cells can be cleared by immune surveillance and influence the fate of neighboring cancer cells mediated by paracrine factors. Induction of cancer cell senescence has been recognized as a novel therapeutic approach; however, how to efficiently induce cancer cell senescence and facilitate cancer cell death by taking advantage of the senescence-associated paracrine factors need to be solved. Here we show that HCCs are repressed by deletion of Survivin, an inhibitor of apoptosis protein. Survivin deficiency induces mitosis defect-caused senescence in HCC cells, which leads to local inflammation and increased TNFα levels. Moreover, both senescent and neighboring non-senescent cancer cells lacking Survivin are hypersensitive to TNFα-triggered cell death. In this project, we plan to analyze whether mitotic defects can induce cancer cell senescence and increase TNFα levels. Also we would like to analyze whether Survivin deficiency-induced cancer cell apoptosis is mediated by TNFα. Finally, by knowing the oncogenic mechanisms controlled by Survivin, we wish to efficiently induce cellular senescence and apoptosis in liver cancer by combined use of mitotic kinase inhibitors and smac mimetics. Hopefully, our findings through this project could serve as a new paradigm for future clinical therapy.

我国肝癌发病率和死亡率高，亟需有效治疗方法。细胞衰老是不可逆的增殖抑制，并可通过旁分泌影响周围癌细胞状态，诱导细胞衰老被认为是癌症治疗新方向。如何有效诱导癌细胞衰老并利用其相关旁分泌机制促进其周围癌细胞死亡是领域内的热点。凋亡抑制蛋白Survivin在有丝分裂和抗凋亡过程有重要作用。我们利用肝脏特异缺失Survivin的小鼠模型，发现靶向Survivin导致肝癌细胞衰老并引起衰老相关的免疫反应，并且缺失Survivin的肝癌细胞对TNFa诱导的凋亡敏感。本项目将进一步阐明Survivin缺失如何导致肝癌细胞衰老和凋亡，揭示有丝分裂抑制剂是否能够诱导肝癌细胞衰老和TNFa表达上调，并鉴定有丝分裂抑制和凋亡诱导物联用是否能够模拟Survivin缺失导致的肝癌细胞衰老和TNFa诱导的凋亡，从而为治疗肝癌提供新思路。

我国肝癌的发病率和死亡率高，缺乏有效的治疗方法。诱导细胞衰老、抑制细胞周期和促进细胞死亡等方法被认为是癌症治疗的新策略。凋亡抑制蛋白Survivin在有丝分裂和抗凋亡过程都有重要作用。我们利用肝脏特异Survivin缺失的小鼠模型，发现靶向Survivin可以导致肝癌细胞衰老并引起衰老相关的免疫反应，并且缺失Survivin的肝癌细胞对TNFa诱导的凋亡更加敏感。通过有丝分裂抑制剂和凋亡诱导物联用能够模拟Survivin缺失导致的肝癌细胞衰老和TNFa诱导的细胞凋亡，从而抑制肿瘤的发展。此外，由于Survivin调控有丝分裂是通过与Borealin、Incenp和Aurora B一起形成染色体乘客复合物实现的，我们利用肝脏特异Borealin缺失的小鼠模型，研究了肝脏特异敲除Borealin能抑制二乙基亚硝胺（DEN）或DN90-b-Catenin/c-Met诱导的肝癌的发生和发展。进一步地，我们建立了筛选抑制Survivin-Borealin相互作用或抑制Survivin-H3T3ph相互作用的筛选系统，尝试筛选新的Survivin抑制剂，从而为治疗肝癌提供新思路。

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