Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling
Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling
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DOI：
10.1038/s41388-022-02334-6
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发表时间：
2022-04-30
期刊：
影响因子：
8
通讯作者：
Li, Binkui
中科院分区：
文献类型：
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作者：
Li, Kai;Niu, Yi;Li, Binkui
热消融术是治疗早期肝癌的主要方法。然而，不充分的消融已被证明会促进HCC进展。E3连接酶已被证实在恶性肿瘤中发挥重要作用。E3连接酶是否参与消融不充分引起的HCC进展仍不清楚。在此，使用RNA测序结合体外功能丧失筛选，我们发现E3连接酶神经元前体细胞表达的发育下调4（Nedd 4）在HCC消融不足组织中上调，并促进HCC细胞迁移。在亚致死热处理后，胃L14介导的N-6-甲基腺苷修饰诱导Nedd 4上调。敲低Nedd 4在体外和体内抑制HCC转移和生长。从机制上讲，Nedd 4通过直接结合TGF-β I型受体（TGFBR 1）并在赖氨酸391处形成K27连接的泛素，增强TGF-β信号转导介导的肿瘤进展。此外，亚致死热处理对肝癌的不利影响是由Nedd 4介导的。临床上，Nedd 4高表达与HCC患者的侵袭性肿瘤表型和不良预后正相关。患者来源的异种移植物（PDX）模型证实了这一结论。总的来说，这项研究表明，不充分消融诱导的Nedd 4在促进HCC进展中起着至关重要的作用，并为HCC提供了一个新的治疗靶点。
Thermal ablation is a main curative therapy for early-stage hepatocellular carcinoma (HCC). However, insufficient ablation has been shown to promote HCC progression. E3 ligases have been approved to play important roles in malignant tumors. Whether E3 ligases are involved in HCC progression caused by insufficient ablation remains unclear. Herein, using RNA-sequencing coupled with an in vitro loss-of-function screen, we found that the E3 ligase Neuronal Precursor cell-expressed Developmentally Downregulated 4 (Nedd4) was upregulated in HCC insufficient ablation tissues and promoted HCC cells migration. The upregulation of Nedd4 was induced by METTL14-mediated N-6-methyladenosine modification after sublethal heat treatment. Knockdown of Nedd4 inhibited HCC metastasis and growth in vitro and in vivo. Mechanistically, Nedd4 enhanced TGF-beta signal transduction mediated tumor progression by directly binding to TGF-beta type I receptor (TGFBR1) and forming K27-linked ubiquitin at Lysine 391. Additionally, the adverse effect on HCC of sublethal heat treatment was mediated by Nedd4. Clinically, high Nedd4 expression was positively correlated with aggressive tumor phenotypes and poor prognosis in HCC patients. Patient-derived xenograft (PDX) model confirmed this conclusion. Collectively, this study demonstrated that Nedd4 induced by insufficient ablation plays a crucial role in promoting HCC progression and provides a novel therapeutic target for HCC.