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

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外文摘要：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 3 5 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 iden-tification 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.

外文关键词：

chemoresistancelncRNARNA interferenceROSchemosensitizer

作者：

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

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作者单位：

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

Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Laboratory of Molecular Oncology,Peking University Cancer Hospital and Institute,Beijing 100142,China

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

Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education),Department of Pathology,Peking University Cancer Hospital and Institute,Beijing 100142,China

Peking University International Cancer Institute,Beijing 100191,China

Institute of Cancer Research,Shenzhen Bay Laboratory,Shenzhen 518132,China

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基金：

国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金

项目编号：

81972842823730828198810182173152

出版年：

2024

DOI：

10.1007/s11427-023-2434-8

中国科学:生命科学(英文版)