肝癌细胞有丝分裂灾难的调控机制及其治疗增敏作用

肝癌生长快，易转移，缺乏有效治疗药物，死亡率极高。绝大部分肝癌组织中p53通路异常失活、TERT或β-catenin通路异常激活。通过诱导有丝分裂灾难（MC）来治疗肿瘤是国际前沿热点。但调控MC的机制不清楚，具有抗癌作用的靶点分子尚待挖掘。我们前期发现了多个可能调控肝癌细胞MC的分子，以此为基础，本项目拟：1)利用肿瘤常见的通路异常，鉴定可靶向调控癌细胞MC的分子，分析单独干预目标分子或联合其他处理对癌细胞MC的诱导作用；2)结合不同遗传背景的肝癌细胞移植瘤及人源肝癌组织移植瘤(PDX)模型，体内验证以目标分子为靶点的抗癌治疗效果，并分析疗效/毒性与癌细胞遗传背景的相关性。3)结合SILAC、RIP、ChIP等技术，发现与目标分子互作的蛋白质/RNA/DNA，阐明目标分子调控MC的分子机制。研究结果将揭示MC调控的新机制，为肝癌靶向治疗提供新靶点，为传统化疗药物的增敏减毒提供新策略

Hepatocellular carcinoma (HCC) grows rapidly and is prone to metastasis，with an extremely high mortality rate due to the lack of effective therapeutic drugs. The majority of HCC tissues display abnormal inactivation of p53 pathway, or activation of TERT or β-catenin signaling. Exploring the therapeutic potential of inducing mitotic catastrophe (MC) in tumor cells is the international frontier of cancer research. However, the regulatory mechanism of MC induction is still unclear, and the therapeutic targets remain to be identified. We have identified a few candidate molecules that may regulate MC. With these findings, we will further conduct the following investigations: 1) Identify the molecules that can specifically regulate MC in HCC cells with inactive p53 or active TERT or β-catenin pathway; Examine the effects of targeting candidate molecule alone or in combination with other treatments on MC induction. 2) Validate the therapeutic effects of targeting candidate molecules in vivo, by using xenografts derived from HCC cell lines with different genetic backgrounds and from clinical specimens of HCC patients (PDX), and analyze the correlation between therapeutic efficacy/toxicity and genetic backgrounds of HCC cells. 3) Identify the protein/RNA/DNA interacting with candidate molecules by SILAC, RIP and ChIP, elucidate the molecular mechanisms underlying MC induction. The results obtained will not only reveal novel mechanisms that regulate MC, but also provide new molecular targets with high efficiency and low toxicity for HCC therapy, and provide new strategies for enhancing sensitivity and reducing toxicity of traditional chemotherapeutic drugs.