SERPINE2 promotes liver cancer metastasis by inhibiting c-Cbl-mediated EGFR ubiquitination and degradation  

作　　者：Shiyu Zhang Xing Jia Haojiang Dai Xingxin Zhu Wenfeng Song Suchen Bian Hao Wu Shinuo Chen Yangbo Tang Junran Chen Cheng Jin Mengqiao Zhou Haiyang Xie Shusen Zheng Penghong Song 

机构地区：[1]Division of Hepatobiliary and Pancreatic Surgery,Department of Surgery,The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,P.R.China [2]National Health Commission Key Laboratory of Combined Multi-organ Transplantation,Hangzhou,Zhejiang,P.R.China [3]Key Laboratory of the Diagnosis and Treatment of Organ Transplantation,Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer,Chinese Academy of Medical Sciences,Hangzhou,Zhejiang,P.R.China [4]Key Laboratory of Organ Transplantation,Research Center for Diagnosis and Treatment of Hepatobiliary Diseases,Hangzhou,Zhejiang,P.R.China [5]State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,P.R.China

出　　处：《Cancer Communications》2024年第3期384-407,共24页癌症通讯（英文）

基　　金：This work was supported by grants from the National Nat-ural Science Foundation of China(82070652 and 81870434);Department of Science and Technology of Zhejiang Province(2020C04003);the Chinese Academy of Medi-cal Sciences(019-I2M-5-030);the Jinan Microecological Biomedicine Shandong Laboratory(JNL-2022007B);the State Key Laboratory for Diagnosis and Treatment of Infectious Diseases(zz202302).

摘　　要：Background:Liver cancer is a malignancy with high morbidity and mortality rates.Serpin family E member 2(SERPINE2)has been reported to play a key role in the metastasis of many tumors.In this study,we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis.Methods:The Cancer Genome Atlas database(TCGA),including DNA methy-lation and transcriptome sequencing data,was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver can-cer.Data from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clin-ical parameters of patients.DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells.RNA sequencing,cytokine assays,immunoprecipitation(IP)and mass spectrometry(MS)assays,protein stability assays,and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer metastasis.Patient-derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib.Results:Based on the public database screening,SERPINE2 was identified as a tumor promoter regulated by DNA methylation.SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer.SERPINE2 promoted liver cancer metas-tasis by enhancing cell pseudopodia formation,cell adhesion,cancer-associated fibroblast activation,extracellular matrix remodeling,and angiogenesis.IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor(EGFR)and its downstream signaling pathways by interacting with EGFR.Mechanistically,SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase,c-Cbl.Additionally,EGFR was activated in liver cancer cells after sorafenib treatment,and SER-PINE2 knockdown-induced EGFR downregulation sig

关 键 词：liver cancer METASTASIS DNA methylation SERPINE2 EGFR C-CBL UBIQUITINATION 

分 类 号：R73-37[医药卫生—肿瘤]