2024年10月15日，重庆医科大学脂质研究中心丁银元特聘教授团队在国际知名期刊《Advanced Science》在线发表了题为“Loss of LRP1 Promotes Hepatocellular Carcinoma Progression via UFL1-Mediated Activation of NF-kB Signaling”的最新研究成果。 郭星娴博士、博士研究生杨帆和刘天艺、陈阿玫博士和刘迪娜博士为该工作的共同第一作者，通讯作者为重庆医科大学丁银元特聘教授。该研究解析了低密度脂蛋白受体相关蛋白1（LRP1）在原发性肝癌（HCC）疾病发生和发展中的作用及其分子机制。

    研究团队首先通过生信分析并结合临床HCC肝脏组织及人HCC细胞系数据发现HCC组LRP1表达水平显著低于对照组。进一步采用过表达或敲降正反两种手段证实，LRP1缺失可增加HCC细胞UFM1特异性连接酶1（UFL1）与N-乙酰葡糖胺糖苷酶（OGA）之间的结合，导致OGA泛素化降解增加及核转录因子NF-kB的O-GlcNAc糖基化水平增高，后者下调Bax表达同时上调Bcl-2转录，促进HCC细胞增殖、迁移并抑制其凋亡。此外，两种HCC小鼠模型均证实敲降LRP1表达促进HCC移植瘤的形成。值得注意的是，研究团队发现过表达LRP1胞内β链短肽（β∆-chain）即能显著抑制HCC细胞的肿瘤生物学活性及HCC移植瘤的形成。

    这一发现加深了我们对于传统脂代谢调控蛋白LRP1在肿瘤发生中新作用的认识，揭示了其在肝癌治疗中的潜在价值，为进一步探索代谢调控与肿瘤发生之间相互作用提供了新的视角，为临床肝癌的发病机制挖掘和精准治疗提供了新的思路。

摘要 Abstract

Low-density lipoprotein receptor-related protein-1 (LRP1) is thought to be correlated with hepatocellular carcinoma (HCC) invasion and metastasis. However, the precise mechanism through which LRP1 contributes to HCC progression remains unclear. Here, lower LRP1 levels are associated with malignant progression, and poor prognosis in patients with HCC is shown. LRP1 knockdown enhances the tumorigenicity of HCC cells in vitro and in vivo, whereas overexpression of either LRP1 or its β-chain has the opposite effect. Mechanistically, LRP1 knockdown promotes the binding of ubiquitin-like modifier 1 ligating enzyme 1 (UFL1) to OGA and accelerates ubiquitin-mediated OGA degradation, leading to increased O-GlcNAcylation of nuclear factor-kappa B (NF-κB) and subsequent inhibition of pro-apoptotic gene expression. Conversely, exogenously expressed truncated β-chain (β∆) stabilizes OGA by disrupting the association between UFL1 and OGA, consequently abolishing the anti-apoptotic effects of O-GlcNAcylated NF-κB. The findings identify LRP1, particularly its β-chain, as a novel upstream control factor that facilitates the stabilization of the OGA protein, thereby suppressing NF-κB signaling and attenuating HCC progression, thus suggesting a novel therapeutic strategy for HCC.

DOI：  https://doi.org/10.1002/advs.202401672 

原文链接：https://onlinelibrary.wiley.com/doi/10.1002/advs.202401672

参考资料：Guo, Xingxian & Yang, Fan & Liu, Tianyi & Chen, Amei & Liu, Dina & Pu, Jiangxia & Jia, Can & Wu, Yuanhong & Yuan, Junfeng & Ouyang, Nan & Herz, Joachim & Ding, Yinyuan. (2024). Loss of LRP1 Promotes Hepatocellular Carcinoma Progression via UFL1‐Mediated Activation of NF‐κB Signaling. Advanced Science. 10.1002/advs.202401672.