The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma

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外文摘要：Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma(HCC).A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed.In this study,we aimed to dissect the underlying mechanism of lenvatinib resistance(LR)and provide effective treatment strategies.We established an HCC model of acquired LR.Cell counting,migration,self-renewal ability,chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells.Molecular and biochemical strategies such as RNA-sequencing,immunoprecipitation,mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms.Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance.We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α(HIF-1 α)pathway activation is responsible for acquired LR in HCC.Phosphorylated non-muscle myosin heavy chain 9(MYH9)at Ser1 943,p-MYH9(Ser1 943),could recruit ubiquitin-specific protease 22(USP22)to deubiquitinate and stabilize HIF-1 α in lenvatinib-resistant HCC.Clinically,p-MYH9(Ser1 943)expression was upregulated in HCC samples,which predicted poor prognosis and LR.A casein kinase-2(CK2)inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro.Therefore,the p-MYH9(Ser1 943)/USP22/HIF-1 α axis is critical for LR and cancer stemness.For the diagnosis and treatment of LR in HCC,p-MYH9(Ser1 943),USP22,and HIF-1 α might be valuable as novel biomarkers and targets.

作者：

Qiaonan Shan、Lu Yin、Qifan Zhan、Jiongjie Yu、Sheng Pan、Jianyong Zhuo、Wei Zhou、Jiaqi Bao、Lincheng Zhang、Jiachen Hong、Jianan Xiang、Qingyang Que、Kangchen Chen、Shengjun Xu、Jingrui Wang、Yangbo Zhu、Bin He、Jingbang Wu、Haiyang Xie、Shusen Zheng、Tingting Feng、Sunbin Ling、Xiao Xu

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作者单位：

Department of Hepatobiliary and Pancreatic Surgery,NHC Key Laboratory of Combined Multi-organ Transplantation,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310058,China

Department of Hepatobiliary and Pancreatic Surgery,The Center for Integrated Oncology and Precision Medicine,Affiliated Hangzhou First People's Hospital,School of Medicine,Westlake University,Hangzhou 310006,China

Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery,Zhejiang Provincial People's Hospital(Affiliated People's Hospital),School of Clinical Medicine,Hangzhou Medical College,Hangzhou 314408,China

Institute of Translational Medicine,Zhejiang University,Hangzhou 310009,China

Zhejiang Cancer Hospital,Hangzhou 310022,China

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基金：

National Key Research and Development Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaProject of Medical and Health Technology Program in Zhejiang Province

项目编号：

2022YFA110680082203070822007268220072792159202822732702024KY853

出版年：

2024

DOI：

10.1038/s41392-024-01963-5

信号转导与靶向治疗(英文)

CSTPCD

ISSN：

年,卷(期)：2024.9(10)