Ribonuclease 7-driven activation of ROS1 is a potential therapeutic target in hepatocellular carcinoma

JOURNAL OF HEPATOLOGY

卷:74

Article

Liu, Chunxiao¹  Zha, Zhengyu¹  Zhou, Chenhao^1,2,3  Chen, Yeh^4,5  Xia, Weiya¹  Wang, Ying-Nai¹  Lee, Heng-Huan¹  Yin, Yirui^2,3  Yan, Meisi^1,6  Chang, Chiung-Wen¹  Chan, Li-Chuan¹  Qiu, Yufan^1,7  Li, Hui^1,2,3  Li, Chia-Wei¹  Hsu, Jung-Mao^1,4,5  Hsu, Jennifer L.¹  Wang, Shao-Chun^4,5  Ren, Ning^2,3  Hung, Mien-Chie^1,4,5 

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[2] Fudan Univ, Dept Liver Surg, Liver Canc Inst, Zhongshan Hosp, Shanghai, Peoples R China

[3] Fudan Univ, Key Lab Carcinogenesis & Canc Invas, Minist Educ, Shanghai, Peoples R China

[4] China Med Univ, Grad Inst Biomed Sci, Res Ctr Canc Biol, Taichung 404, Taiwan

[5] China Med Univ, Ctr Mol Med, Taichung 404, Taiwan

[6] Harbin Med Univ, Dept Pathol, Harbin 150081, Heilongjiang, Peoples R China

[7] Tianjin Med Univ, Dept Breast Canc 3, China Tianjin Breast Canc Prevent, Treatment & Res Ctr,Canc Inst & Hosp,Natl Clin Re, Tianjin, Peoples R China

关键词: ROS1;    Ribonuclease 7;    Plasma biomarker;    Hepatocellular carcinoma;    Crizotinib;    Cancer;    Tyrosine kinase;    Signaling;    Treatment stratification;   

DOI  :  10.1016/j.jhep.2020.09.030

来源: Elsevier

【 摘 要 】

Background & Aims: There are currently limited therapeutic options for hepatocellular carcinoma (HCC), particularly when it is diagnosed at advanced stages. Herein, we examined the pathophysiological role of ROS1 and assessed the utility of ROS1-targeted therapy for the treatment of HCC. Methods: Recombinant ribonucleases (RNases) were purified, and the ligand-receptor relationship between RNase7 and ROS1 was validated in HCC cell lines by Duolink, immunofluores-cence, and immunoprecipitation assays. Potential interacting residues between ROS1 and RNase7 were predicted using a protein-protein docking approach. The oncogenic function of RNase7 was analyzed by cell proliferation, migration and inva-sion assays, and a xenograft mouse model. The efficacy of anti-ROS1 inhibitor treatment was evaluated in patient-derived xenograft (PDX) and orthotopic models. Two independent pa-tient cohorts were analyzed to evaluate the pathological rele-vance of RNase7/ROS1. Results: RNase7 associated with ROS1's N3-P2 domain and promoted ROS1-mediated oncogenic transformation. Patients with HCC exhibited elevated plasma RNase7 levels compared with healthy individuals. High ROS1 and RNase7 expression were strongly associated with poor prognosis in patients with HCC. In both HCC PDX and orthotopic mouse models, ROS1 inhibitor treatment markedly suppressed RNase7-induced tumorigenesis, leading to decreased plasma RNase7 levels and tumor shrinkage in mice. Conclusions: RNase7 serves as a high-affinity ligand for ROS1. Plasma RNase7 could be used as a biomarker to identify patients with HCC who may benefit from anti-ROS1 treatment. Lay summary: Receptor tyrosine kinases are known to be involved in tumorigenesis and have been targeted therapeuti-cally for a number of cancers, including hepatocellular carcinoma. ROS1 is the only such receptor with kinase activity whose ligand has not been identified. Herein, we show that RNase7 acts as a ligand to activate ROS1 signaling. This has important path-ophysiological and therapeutic implications. Anti-ROS1 in-hibitors could be used to treatment patients with hepatocellular carcinoma and high RNase7 levels. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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