Abstract
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 N6-methyladenosine modification after sublethal heat treatment. Knockdown of Nedd4 inhibited HCC metastasis and growth in vitro and in vivo. Mechanistically, Nedd4 enhanced TGF-β signal transduction mediated tumor progression by directly binding to TGF-β 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.
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Funding
National Natural Science Foundation of China (No. 81772625, No. 81972301 and No. 81802421). Guangzhou Science and Technology Program of China (No. 201804020093).
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Conceptualization: BL and YY. Methodology: KL, YN, YY and YS, Investigation: CZ and ZQ, Visualization: ZH and DZ. Statistical analysis: ZL and KL. Supervision: BL, YY, and CZ. Writing—original draft: KL and YN. Writing—review & editing: BL, WH, and JQ.
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This study complied with the standards of the 1975 Declaration of Helsinki and the experiments were approved by the Ethics Committee of Sun Yat-sen University Cancer Center (Approval No: GZR2017-116). The animal experiments were approved by the institutional ethics committee of Sun Yat-sen University, Guangzhou, China (Approval No: L102012019120E).
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Li, K., Niu, Y., Yuan, Y. et al. Insufficient ablation induces E3-ligase Nedd4 to promote hepatocellular carcinoma progression by tuning TGF-β signaling. Oncogene 41, 3197–3209 (2022). https://doi.org/10.1038/s41388-022-02334-6
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DOI: https://doi.org/10.1038/s41388-022-02334-6
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