PP2A介导MYC相关锌指蛋白在肝细胞恶性转化中的作用机制研究

With the increased tumor burden caused by chemical carcinogens, it has become the most important problem to solve the prevention and treatment of tumors caused by chemicals. Studies have confirmed that protein phosphatase 2A (PP2A) plays an important role in chemical-induced cell transformation by regulating phosphorylation of key proteins in multiple signaling pathways. Preliminary experiments show that the activity inhibition of PP2A results in alteration of epithelial-mesenchymal transition (EMT) related factors and cell migration in aflatoxin (AFB1) transformed liver cells, suggesting that PP2A may be involved in the EMT process. In view of our previous study that MYC associated zinc finger protein (MAZ) promotes the invasion and metastasis of hepatocellular carcinoma (HCC) by inducing EMT, we speculate that PP2A might mediate MAZ phosphorylation in the metastasis of chemical-transformed liver cells. On the basis of HCC high incidence in Guangxi, the downstream targets and signaling pathways of MAZ in EMT will be screened by whole genome expression profile sequencing. In addition, we aim to explore the role of MAZ phosphorylation in liver cell malignant transformation and EMT, and to further clarify the role and mechanism of PP2A in mediating MAZ dephosphorylation in liver cell malignant transformation and metastasis. We will provide a theoretical basis and clues for MAZ as a new target for the prevention and treatment of HCC.

随着日益增加的化学致癌物所导致的日益加重的肿瘤负担，如何预防和治疗化学物所致肿瘤，已成为迫切解决的关键问题。研究证实，蛋白磷酸酶2A（PP2A）调节多条信号通路中关键蛋白的磷酸化水平，在化学物诱导细胞恶性转化过程中发挥重要作用。预实验结果显示PP2A酶活性抑制后，黄曲霉毒素（AFB1）诱导转化的肝细胞侵袭转移能力及上皮-间质转化（EMT）相关因子的表达发生改变。鉴于前期研究发现MYC相关锌指蛋白（MAZ）介导EMT促进肝癌的侵袭转移，我们推测PP2A可能介导MAZ参与肝细胞恶性转化EMT过程。本项目拟利用广西肝癌高发这一现场，采用基因芯片技术等筛选MAZ调控的EMT下游靶点及相关信号通路，探索MAZ磷酸化修饰在肝细胞恶性转化及EMT过程中的功能，进一步阐述特异的PP2A全酶介导MAZ去磷酸化及参与肝细胞恶性转化和转移的分子调控机制，为MAZ是否可作为防治肝癌新的有效靶点提供理论依据和线索。

随着日益增加的化学致癌物所导致的日益加重的肿瘤负担，如何预防和治疗化学物所致肿瘤，已成为迫切解决的关键问题。肝癌是我国最常见的恶性肿瘤之一，广西省的肝癌发病率和死亡率均明显高于全国水平，在各种肿瘤中长期排名第一。阐述肝癌恶性转化和转移的机制及寻找其中的关键靶向分子是防治肝癌的关键。本项目通过四年的研究，发现PP2A抑制剂冈田酸通过抑制PP2A活性促进肝癌细胞的上皮-间质转化；MAZ可能通过调控ZEB1的表达诱导EMT进程，进而促进肝癌的恶性转移；冈田酸对阿莫西林诱导的大鼠肝损伤具有保护作用；综述了PP2A在细胞自噬中的研究进展，MAZ在恶性肿瘤中的作用，以及TRIMs家族蛋白在肿瘤中的研究进展；CMTM2蛋白在肝癌组织中低表达，且通过诱导EMT参与调控肝癌的侵袭转移；CMTM1在肝癌组织中的高表达可提示肝癌患者的预后；CMTM4和POM121可作为肺癌临床判断预后的分子标志物；m6A去甲基化酶FTO在甲状腺癌中的表达可预示肿瘤的进展。相关研究结果发表SCI论文8篇和SCI综述3篇，协同培养硕士生4名；参加国内各种学术交流会议4人次。获得了2020年国家自然科学基金地区项目1项和2020年广西自然科学基金重点项目1项。