Targeting lncRNA16 by GalNAc-siRNA conjugates facilitates chemotherapeutic sensibilization via the HBB/NDUFAF5/ROS pathway  

作　　者：Yanfang Liu Yan Wang Bing Liu Wenzhong Liu Yuanyuan Ma Yiren Cao Shi Yan Panpan Zhang Lixin Zhou Qimin Zhan Nan Wu 

机构地区：[1]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Department of Thoracic Surgery II,Peking University Cancer Hospital and Institute,Beijing 100142,China [2]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Laboratory of Molecular Oncology,Peking University Cancer Hospital and Institute,Beijing 100142,China [3]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Department of Thoracic Oncology II,Peking University Cancer Hospital and Institute,Beijing 100142,China [4]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education),Department of Pathology,Peking University Cancer Hospital and Institute,Beijing 100142,China [5]Peking University International Cancer Institute,Beijing 100191,China [6]Institute of Cancer Research,Shenzhen Bay Laboratory,Shenzhen 518132,China

出　　处：《Science China(Life Sciences)》2024年第4期663-679,共17页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China (81972842, 82373082, 81988101, 82173152)

摘　　要：Chemoresistance is a significant barrier to effective cancer treatment.Potential mechanisms for chemoresistance include reactive oxygen species(ROS)accumulation and expression of chemoresistance-promoting genes.Here,we report a novel function of lncRNA16 in the inhibition of ROS generation and the progression of chemoresistance.By analyzing the serum levels of lncRNA16 in a cohort of 35 patients with non-small cell lung cancer(NSCLC)and paired serum samples pre-and post-treatment from 10 NSCLC patients receiving neoadjuvant platinum-based chemotherapy,performing immunohistochemistry(IHC)assays on 188 NSCLC tumor samples,using comprehensive identification of RNA-binding proteins by mass spectrometry(ChIRP-MS)assays,as well as RNA immunoprecipitation(RIP)and RNA pull-down analyses,we discovered that patients with increased serum levels of lncRNA16 exhibited a poor response to platinum-based chemotherapy.The expression of hemoglobin subunit beta(HBB)and NDUFAF5 significantly increases with the development of chemoresistance.LncRNA16 binds to HBB and promotes HBB accumulation by inhibiting autophagy.LncRNA16 can also inhibit ROS generation via the HBB/NDUFAF5 axis and function as a scaffold to facilitate the colocalization of HBB and NDUFAF5 in the mitochondria.Importantly,preclinical studies in mouse models of chemo-resistant NSCLC have suggested that lncRNA16 targeting by trivalent N-acetylgalactosamine(GalNAc)-conjugated siRNA restores chemosensitivity and results in tumor growth inhibition with no detectable toxicity in vivo.Overall,lncRNA16 is a promising therapeutic target for overcoming chemoresistance,and the combination of first-line platinum-based chemotherapy with lncRNA16 intervention can substantially enhance anti-tumor efficacy.

关 键 词：CHEMORESISTANCE lncRNARNA interference ROS CHEMOSENSITIZER 

分 类 号：R730.5[医药卫生—肿瘤]