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

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Abstract

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.

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Acknowledgement

This work was supported by the National Natural Science Foundation of China (81972842, 82373082, 81988101, 82173152).

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Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Bei**g), Department of Thoracic Surgery II, Peking University Cancer Hospital and Institute, Bei**g, 100142, China

    Yanfang Liu, Bing Liu, Yuanyuan Ma, Shi Yan & Nan Wu

  2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Bei**g), Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Bei**g, 100142, China

    Yan Wang, Wenzhong Liu, Yiren Cao & Qimin Zhan

  3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Bei**g), Department of Thoracic Oncology II, Peking University Cancer Hospital and Institute, Bei**g, 100142, China

    Panpan Zhang

  4. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Bei**g, 100142, China

    Lixin Zhou

  5. Peking University International Cancer Institute, Bei**g, 100191, China

    Qimin Zhan

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

    Qimin Zhan

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  1. Yanfang Liu
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The author(s) declare that they have no conflict of interest. The Ethics Committee of Peking University Cancer Hospital and Institute approved all procedures performed in studies involving human participants (2020KT50) and were by the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All animal protocols were approved by the Animal Care and Use Committee of the Peking University Cancer Hospital & Institute (EAEC 2018–11).

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Liu, Y., Wang, Y., Liu, B. et al. Targeting lncRNA16 by GalNAc-siRNA conjugates facilitates chemotherapeutic sensibilization via the HBB/NDUFAF5/ROS pathway. Sci. China Life Sci. 67, 663–679 (2024). https://doi.org/10.1007/s11427-023-2434-8

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