PAPSS1介导MAGL乙酰化修饰调控NF-κB信号通路影响α干扰素抗肝癌敏感性的作用机制研究

We previously evidenced that interferon alpha (IFN-α) can effectively inhibit the metastasis and recurrence of hepatocellular carcinoma (HCC), however, there are differences in individual sensitivity and the specific mechanism is still not clear. Hence, it is urgently needed to elucidate the anti-tumor mechanism of IFN-α, and further establish a molecular model to predict sensitive populations, which would provide clinical benefit. In our previous studies, we found that 3'-phosphoadenosine 5'-phosphosulfate synthase 1(PAPSS1), which is closely related to the efficacy of IFN-α in HCC, can promote the acetylation of monoacylglycerol lipase (MAGL). In addition, based on our clearly defined notion that MAGL regulates NF-κB signal to promote the progression of HCC, we speculated PAPSS1 might affect the sensitivity of IFN-α therapy in HCC. In this study, the following topics will be studied: 1. The effect of PAPSS1-mediated MAGL acetylation on the sensitivity of IFN-α therapy; 2. The specific molecular mechanism by which PAPSS1 affect the sensitivity of IFN-α; 3. The clinical significance of PAPSS1 in IFN-α therapy. This project will enable us to further understand the role and significance of PAPSS1 in HCC progression and IFN-α therapy, and further validate the conclusion that PAPSS1 contributes to the construction of the predictive molecular model for the outcomes of IFN-α in HCC.

我们通过动物及临床实验发现α干扰素能有效抑制肝癌转移复发，但存在个体敏感性差异，具体机制不清。因此，详细阐明α干扰素抗肝癌机制，建立预测敏感人群分子模型，将使临床获益。前期研究证实，3-磷酸腺苷-5-磷酸硫酰合成酶（PAPSS1）不仅与α干扰素疗效相关，而且促进单酰基甘油酯酶（MAGL）乙酰化修饰。同时，基于我们已明确的“MAGL调控NF-κB表达促进肝癌进展”，推测：调控PAPSS1有可能影响α干扰素治疗敏感性。本课题将对如下科学问题进行研究：1.PAPSS1介导MAGL乙酰化修饰对α干扰素抗肝癌敏感性的影响；2.PAPSS1影响α干扰素敏感性的具体分子机制；3.PAPSS1影响α干扰素敏感性的临床意义。对这些问题的解答，将使我们在了解PAPSS1影响α干扰素敏感性分子机制的基础上，进一步认识其在肝癌进展中的作用和意义，以及PAPSS1和下游分子作为构建α干扰素疗效预测分子模型的可行性。

转移复发限制肝癌术后患者生存率进一步提高，临床匮乏有效药物。通过动物及临床实验我们发现α干扰素能有效抑制肝癌转移复发，但存在个体敏感性差异，具体机制不清。因此，详细阐明α干扰素抗肝癌机制，建立预测敏感人群分子模型，将使临床获益。前期研究证实，3-磷酸腺苷-5-磷酸硫酰合成酶（PAPSS1）不仅与α干扰素疗效相关，而且促进单酰基甘油酯酶（MAGL）乙酰化修饰。同时，基于我们已明确的“MAGL调控NF-κB表达促进肝癌进展”，推测：调控PAPSS1有可能影响α干扰素治疗敏感性。本课题将对如下科学问题进行研究：1.PAPSS1介导MAGL乙酰化修饰对α干扰素抗肝癌敏感性的影响；2.PAPSS1影响α干扰素敏感性的具体分子机制；3.PAPSS1影响α干扰素敏感性的临床意义。对这些问题的解答，将使我们在了解PAPSS1影响α干扰素敏感性分子机制的基础上，进一步认识其在肝癌进展中的作用和意义，以及PAPSS1和下游分子作为构建α干扰素疗效预测分子模型的可行性。