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

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 

机构地区：[1]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 [2]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 [3]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 [4]Institute of Translational Medicine,Zhejiang University,Hangzhou,310009,China [5]Zhejiang Cancer Hospital,Hangzhou,310022,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第10期4614-4627,共14页信号转导与靶向治疗（英文）

基　　金：National Key Research and Development Program of China(2022YFA1106800),National Natural Science Foundation of China(82203070,82200726,82200727,92159202 and 82273270);Project of Medical and Health Technology Program in Zhejiang Province(2024KY853).

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-1α)pathway activation is responsible for acquired LR in HCC.Phosphorylated non-muscle myosin heavy chain 9(MYH9)at Ser1943,p-MYH9(Ser1943),could recruit ubiquitin-specific protease 22(USP22)to deubiquitinate and stabilize HIF-1αin lenvatinib-resistant HCC.Clinically,p-MYH9(Ser1943)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(Ser1943)/USP22/HIF-1αaxis is critical for LR and cancer stemness.For the diagnosis and treatment of LR in HCC,p-MYH9(Ser1943),USP22,and HIF-1αmight be valuable as novel biomarkers and targets.

关 键 词：USP22 HEPATOCELLULAR diagnosis 

分 类 号：R735.7[医药卫生—肿瘤]