胞核paraspeckle参与炎症诱导肝癌发生的机制研究

Hepatocellular carcinoma (HCC) is especially prevalent in China. Inflammatory cytokine——interleukin-6 (IL-6) plays an important role in HCC carcinogenesis. In our preliminary studies, we have found that IL-6 promoted the formation of paraspeckle bodies, a kind of membraneless substructure in nucleus containing lncRNA neat1_2 as scaffold and some other RNA binding proteins such as NONO and SFPQ. We further revealed that the blockage of paraspeckle formation by lncRNA neat1_2 knockdown inhibited IL-6-induced ROS production, DNA damage, cell invasion and anti-apoptosis effect in HCC cell lines. Therefore, our future study aims to further confirm the role of paraspeckle in IL-6-induced inflammation and carcinogenesis of HCC. Also, the interaction between lncRNA neat1_2 and the RNA binding proteins in paraspeckle bodies will be investigated and the mechanisms underlying the effect of paraspeckle bodies as well as lncRNA neat1_2 will be explored. Our work will broaden our knowledge of inflammation and carcinogenesis of HCC and suggest new mechanisms and intervention approaches in HCC.

肝细胞癌严重威胁我国人民健康。细胞炎症因子白介素6(IL-6)在肝癌的发生发展中扮演了重要角色。前期研究中我们发现IL-6刺激肝癌细胞后，细胞核内亚结构paraspeckle小体形成增多。Paraspeckle小体是一类由lncRNAneat1_2作为脚手架结合多种RNA结合蛋白形成的核内无膜亚结构。后续试验发现通过敲低lncRNAneat1_2表达而抑制paraspeckle亚结构形成可阻止IL-6介导的肝癌细胞恶变效应，如细胞内DNA损伤、细胞侵袭增强、抑制细胞凋亡等。本课题将进一步明确paraspeckle及其重要组分lncRNAneat1_2在IL-6诱导的肝癌细胞恶性分化中的作用，明确其作用方式及机制，并在动物模型中验证paraspeckle及lncRNAneat1_2在炎症诱导肝癌发生中的功能，以期拓宽对肝脏炎癌转化机制的认识，为肝癌早期诊治提供新的潜在靶点。

细胞炎症因子白介素6在肝癌的发生发展中扮演了重要角色。前期研究中我们发现IL-6促进了肝癌细胞系中paraspeckle的形成。本项目研究发现，通过敲低表达paraspeckle的组成成分NEAT1_2或者NONO进而破坏paraspeckle，能够抑制IL-6诱导的STAT3磷酸化及肝癌细胞侵袭、细胞周期进展及存活。机制方面，paraspeckle通过结合PRDX5mRNA，将PRDX5 mRNA存留在核内从而使PRDX5蛋白表达减少，进而使PRDX5蛋白与STAT3蛋白相互作用阻抑STAT3蛋白磷酸化的作用受到抑制。另外，可以通过其去氧化活性抑制DNA损伤及凋亡的GSTP1蛋白也被发现存留于IL-6诱导的paraspeckle中。因此，paraspeckle可通过存留PRDX5 mRNA和GSTP1蛋白促进了IL-6诱导的肝癌细胞的DNA损伤。本研究结果表明paraspeckle可以抑制IL-6/STAT3信号并滞留DNA损伤的抑制因子从而促进IL-6诱导的肝癌细胞进展。研究结果拓宽了对肝脏炎癌转化机制的认识，可能为肝癌早期诊治提供新的潜在靶点。