NF-YA/CDCA8轴通过调控MAPK信号通路促进肝癌的进展

       肝癌是最常见的消化道癌症之一。高达三分之二的患者首次被诊断即为癌症中晚期。患者即使接受手术，术后也很快复发和转移。因此，深入研究肝癌的发生发展和转移机制，探索肝癌恶性演进的标志物是当前肝癌研究领域的重点。
       细胞分裂周期相关8（CDCA8）基因是脊椎动物染色体乘客复合物的重要组成部分，它在多种肿瘤中高表达并促进肿瘤进展。然而，目前CDCA8在肝癌中的作用机制尚不完全清楚。本研究旨在通过分析CDCA8的表达与肝癌细胞增殖和转移的关系，揭示CDCA8在肝癌中的作用，并探索及其上下游信号通路。我们在收集的临床标本中验证了CDCA8在肝癌组织中的表达显著高于癌旁组织。通过TCGA数据库我们发现CDCA8在肝癌中高表达，并且CDCA8的高表达与肝癌患者不良预后显著相关。免疫组织化学染色实验证实CDCA8的高表达也提示与患者较短的总生存期和无病生存期相关。通过CCK8细胞增殖实验、克隆形成实验、细胞迁移和侵袭实验，我们发现敲低CDCA8的表达可以抑制PLC/PRF/5和HepG2等肝癌细胞的体外增殖和浸润。裸鼠皮下瘤以及尾静脉肺转移瘤模型实验结果提示CDCA8促进肝癌细胞在裸鼠体内的生长和肺部转移。
       在此基础上，针对敲低CDCA8的细胞系进行RNA测序，结果提示CDCA8多个下游潜在靶点。细胞系验证得到NECAP2、TPM3和USP13是CDCA8关系最为密切相关的下游分子，数据库分析提示这三个基因与患者不良预后呈显著相关; 富集分析显示，CDCA8的表达可能影响MAPK信号通路。蛋白印迹实验进一步验证了CDCA8促进MEK/ERK的磷酸化发挥促癌效应。此外，我们通过生信分析以及实验验证转录因子NF-YA可能是调控CDCA8的上游基因，更为重要的是，干扰CDCA8可以逆转NF-YA的促癌作用。综上，本研究发现NF-YA/CDCA8信号轴通过激化MEK/ERK磷酸化促进肝癌增殖转移。

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