αTAT1介导的微管乙酰化修饰驱动炎症小体活化促进肝癌转移的作用及机制研究

最新研究表明，微管翻译后修饰可能是肿瘤等迟发或缓进型疾病完美的候选风险因子。申请人前期研究发现，乙酰化微管参与肝癌侵袭转移。但是，微管乙酰化修饰的调控机制及其在肝癌中的作用尚不明确。αTAT1是最关键的微管乙酰化酶。那么，αTAT1是否参与肝癌侵袭转移？目前尚未见研究报道。肝癌是典型的炎症驱动型肿瘤，炎症小体相关蛋白正确的亚定位及转位是炎症小体活化的关键。那么，作为细胞器转运及胞内物质运输“高速公路”的乙酰化微管，是否参与肝癌炎症小体活化？目前尚不清楚。为此，本课题拟进一步探索：①验证αTAT1与肝癌侵袭转移的相关性；②证实αTAT1介导的微管乙酰化修饰驱动炎症小体活化；③阐明IL-1β-αTAT1-乙酰化微管正反馈环的调控机制及在肝癌炎症微环境中的作用；④探讨应用IL-1β单克隆抗体ACZ885的潜在转化价值。期待通过本课题为抑制肝癌转移提供新的线索及思路。

Microtubule posttranslational modifications may be perfect candidates for risk factors of late-onset or slow-developing diseases such as cancers. Our latest study showed that acetylated microtubules were involved in the invasion and metastasis of hepatocellular carcinoma (HCC). However, the role and regulatory mechanism of microtubule acetylation in HCC are still poorly understood. Microtubule acetylation is tightly controlled by the enzymatic activities of multiple acetyltransferases and is negatively regulated by the activities of the deacetylases. αTAT1 is the major acetyltransferase that catalyzes microtubule acetylation. Whether this process is involved in promoting malignant progress of HCC remains unclear. HCC is a prototype inflammation-driven tumor. Inflammasome activation is closely related to its sub-cellular localization and translocation. Acetylated microtubules is called the "highway" of intracellular transport and organelle assembly. Whether it is involved in the inflammasome activation in HCC, however, is unclear. Therefore, this project intends to be completed as follows: a. To explore the correlation between αTAT1 and HCC metastasis; b. To clarify the mechanism of inflammasome activation drived by αTAT1-mediated microtubule acetylation; c. To clarify the regulatory mechanism of a novel positive feedback loop of IL-1β-αTAT1-acetylated microtubule and its functions in the inflammatory microenvironment of HCC; d. To explore the potential translational values of IL-1βmonoclonal antibody ACZ885 in targeting IL-1β-αTAT1-acetylated microtubule pathway. In conclusion, we propose that αTAT1-mediated microtubule acetylation drives inflammasomes activation in HCC invasion and metastasis, which may provide new targets and treatment strategies for inhibiting the malignant progress of HCC.