细胞衰老抑制基因对NOLC1的调控机制及生物学意义探究

Cell senescence and carcinogenesis are closely related, understanding of the relationship between carcinogenesis and senescence can be an important prerequisite for cancer prevention and treatment. The nucleolus is a key organelle that is responsible for the synthesis of rRNA and assembly of ribosomal subunits, which is related to cell senescence and tumor progression, and has been a potential target of cancer therapy. Cellular senescence-inhibited gene (CSIG) was cloned in our laboratory, overexpression of CSIG can significantly delay cell senescence. Besides, the expression of CSIG is enhanced in hepatocellular carcinoma (HCC) and promotes HCC cell proliferation and tumor growth. We recently found that CSIG could affect the stability of NOLC1 mRNA and decreased the expression of NOLC1, and thus disturbed the nucleolus structure and inhibited rRNA synthesis. Therefore, we will focus on in-depth understanding of the underline molecular mechanism of how CSIG influenced the NOLC1 mRNA stability and provide clues to explain the relationship between aging and tumor.

衰老与肿瘤的发生息息相关，进一步了解它们之间的关系可为肿瘤防治提供新思路。核仁是rRNA合成和加工的主要场所，广泛参与了细胞衰老及肿瘤的发生发展过程，并成为肿瘤治疗的潜在重要靶标。核仁蛋白NOLC1对核仁结构维持及rRNA合成具有重要作用。细胞衰老抑制基因(cellular senescence-inhibited gene，CSIG)由我室自主克隆，并发现其可影响细胞衰老进程。此外，CSIG在肝癌中表达升高并促进肝癌细胞增殖和肿瘤形成。近来我们发现CSIG可影响NOLC1 mRNA的稳定性进而影响NOLC1蛋白质水平，从而扰乱核仁结构并影响rRNA合成。本课题籍此进一步探讨细胞衰老及肿瘤之间的联系以及CSIG对rRNA合成影响的具体机制。

细胞衰老抑制基因(CSIG)是本实验室发现并自主克隆的细胞衰老相关基因，既往研究成果提示CSIG 可能在衰老及肿瘤的发生发展过程中发挥重要作用。本课题在CSIG对核仁和螺旋体磷蛋白1(NOLC1)调控的作用机制研究中，利用多种细胞模型和小鼠组织明确了CSIG与NOLC1负相关的调节关系及其分子机制，探索了CSIG与NOLC1的相互作用对rRNA合成的影响，揭示了CSIG-NOLC1-rRNA通路在细胞衰老中发挥的调节作用，并进一步利用动物实验证实了NOLC1对肿瘤细胞增殖的抑制作用。在CSIG-NOLC1下游信号通路研究中，发现端粒重复序列结合因子2(TRF2)是CSIG-NOLC1通路的靶分子之一，CSIG可与TRF2相互作用并介导后者在核仁和胞核间的穿梭。此外，课题研究还进一步明确了TRF2参与核仁应激诱导的rRNA抑制和细胞周期停滞。课题成果为研究细胞衰老的调控机制、肝癌与细胞衰老的相互关系以及肝癌的治疗提供新的思路和理论基础。