Nucleostemin通过调控PRC1复合物促进肝癌干细胞性和端粒稳定性的机制研究

Cancer stemness plays a pivotal role in facilitating liver cancer malignancy and dismal prognosis. Our preliminary study revealed that Nucleostemin (NS), a novel stem marker protein, may directly bind to Bmi1 and Ring1b, the catalytic subunits of Polycomb Repressive Complex 1 (PRC1), and promote the stability of the two proteins, whose molecular mechanism is tightly linked to liver cancer stemness and telomere stability. On the basis of these findings, our group propose the hypothesis that NS binds to and stabilizes Bmi1 and Ring1b, promotes the expression of stem cell related proteins and TERT mediated by PRC1 transcriptional regulatory complex, and consequently leads to NS-mediated liver cancer stemness and telomere stability. Our project aims to first investigate the association among NS, Bmi1 and Ring1b, as well as the mechanism underlying NS-mediated stabilization of Bmi1 and Ring1b. Next, we will analyze the involvement of NS in modulating PRC1 activity and consequent histone modifications. Moreover, we will examine the effect of NS in the expression of PCR1 downstream targets, the expansion of liver cancer stem cells and telomere stability. Finally, using xenograft mice model and clinical HCC specimens, we will determine the relationship between NS-modulated Bmi1, Ring1b and TERT expression and liver cancer malignant growth as well as the prognosis of HCC patients. Our project may help clarify the regulatory mechanisms underlying liver cancer stemness and telomere stability, and provide novel promising therapeutic targets for the development of liver cancer stem cell-based therapy.

肿瘤干细胞性是导致肝癌恶性进程的重要原因。课题组前期研究发现一个新型的干细胞标志物NS可结合并促进多梳抑制复合物1（PRC1）催化亚基Bmi1和Ring1b的稳定性，这一机制和肝癌干细胞性和端粒稳定性存在密切联系。基于此，课题组提出假说：NS通过增强Bmi1和Ring1b的稳定性，促进PRC1转录调控复合物介导的干细胞相关蛋白及TERT的表达，从而增强肝癌干细胞性和端粒稳定性，导致肝癌的进程。课题组拟首先研究NS稳定Bmi1和Ring1b的机制；并分析NS对PRC1活性及转录调控的影响；进而分析NS对PRC1复合物下游干细胞基因及TERT表达以及对肝癌干细胞扩增和端粒稳定性的影响；最后课题组拟在裸鼠体内和临床组织标本中研究上述机制与肝癌体内恶性生长及病人预后的关联性。本课题将有助于阐明肝癌干细胞和端粒稳定性的调控机制，并为靶向肝癌干细胞和肝癌治疗提供新的有前景的治疗靶标。

肿瘤干细胞性是导致肝癌恶性进程的重要原因。一个新型的干细胞标志物NS可结合并促进多梳抑制复合物1（PRC1）催化亚基Bmi1和Ring1b的稳定性，这一机制和肝癌干细胞性和端粒稳定性存在密切联系。因此，我们提出假说：NS通过增强Bmi1和Ring1b的稳定性，促进PRC1转录调控复合物介导的干细胞相关蛋白及TERT的表达，从而增强肝癌干细胞性和端粒稳定性，导致肝癌的进程。在本项目的资助下，研究发现，NS在肝癌组织相比于癌旁组织有明显的表达上调。NS在肝癌组织中与主要的衰老标志物p21的表达存在明显的负相关性。免疫沉淀表明NS和Bmi1存在相互作用。免疫荧光共聚焦表明NS和Bmi1在肝癌细胞中存在部分共定位。干扰NS可以诱导肝癌细胞发生衰老表型。过表达Bmi1可以回复干扰NS诱导的衰老表型。RNA测序表明干扰NS可以促进多种衰老相关基因的表达上升。GSEA分析测序结果证实了衰老通路发生了明显的上调。本研究将有助于阐明肝癌干细胞和端粒稳定性的调控机制，并为靶向肝癌干细胞和肝癌治疗提供新的有前景的治疗靶标。

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