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自噬相关基因5通过影响p53信号通路促进肝细胞癌发展

ATG5 interacts with the p53 signaling pathway to promote the development of hepatocellular carcinoma

    摘要
  • 摘要:
    目的 探讨自噬相关基因5（autophagy-related gene 5, ATG5）在肝细胞癌（hepatocellular carcinoma, HCC）进展中的作用及其影响的下游信号通路。
    方法 通过肿瘤基因组图谱（The Cancer Genome Atlas, TCGA）数据库查找ATG5在HCC患者的组织表达及其亚组的差异分析。采用免疫印迹法明确ATG5在HCC细胞系中的表达水平。通过CCK-8实验、划痕实验和Transwell实验观察敲减ATG5基因后对HCC细胞系（HCCLM3和MHCC97-H）增殖、迁移和侵袭功能的变化。在HCC细胞系MHCC97-H敲减ATG5基因后，使用有参转录组测序分析下游相关信号通路的变化。
    结果 TCGA数据库分析显示，在mRNA水平，ATG5在HCC组织的表达明显高于正常肝组织（P＜0.0001），HCC 3期患者的ATG5水平高于1期患者的水平（P＝0.013），p53变异组患者癌组织的ATG5水平高于非变异组（P＜0.0001）。免疫印迹结果显示，与正常肝细胞L02相比，ATG5蛋白水平在检测的HCC细胞株中均明显高表达。将ATG5基因敲减后发现，HCC细胞的增殖、迁移、侵袭的能力下降，有参测序发现其明显影响p53信号通路的基因表达，富集分析发现与细胞周期有关，同时影响了自噬相关基因的差异表达。
    结论 ATG5下调可抑制HCC细胞的增殖、迁移和侵袭，同时可通过影响p53信号通路促进HCC发展。

     

    Abstract:
    Objective To explore the role and the signaling pathways of autophagy-related gene 5 (ATG5) in hepatocellular carcinoma (HCC).
    Methods The Cancer Genome Atlas (TCGA) database was used to investigate the expression of ATG5 in HCC tissues and differential analysis in its subgroups. Western blotting was performed to clarify its expression in HCC cell lines. Cell Counting Kit-8, wound healing assay, and Transwell assay were employed to unveil the function of ATG5 in HCCLM3 and MHCC97-H cells. RNA Sequencing and differentially expressed genes analysis were performed to discover the relevant signaling pathways.
    Results TCGA database showed that the mRNA expression of ATG5 was significantly higher in HCC tissues compared with that in normal liver tissues (P < 0.000 1), and higher expression in patients at stage 3 than those at stage 1 (P＝0.013). Furthermore, its expression was higher in patients with p53 mutation (P < 0.000 1). Western blotting results showed that the levels of ATG5 were significantly higher in all tested HCC cell lines than L02. Knockdown of ATG5 was found to inhibits HCC cell proliferation, migration, and invasion, and it was also revealed to affect the expression of p53-related signaling pathway, cell cycle and autophagy-related pathway.
    Conclusions ATG5 downregulation inhibited the function of HCC cells and promoted HCC progression by affecting the p53 signaling pathway.

     

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