Targeting lncRNA16 by GalNAc-siRNA conjugates facilitates chemotherapeutic sensibilization via the HBB/NDUFAF5/ROS pathway
© 2023. Science China Press..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
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| Enthalten in: |
Science China. Life sciences - 67(2024), 4 vom: 25. Apr., Seite 663-679 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Yanfang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.04.2024 Date Revised 08.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s11427-023-2434-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366459260 |
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| 245 | 1 | 0 | |a Targeting lncRNA16 by GalNAc-siRNA conjugates facilitates chemotherapeutic sensibilization via the HBB/NDUFAF5/ROS pathway |
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| 520 | |a © 2023. Science China Press. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Wang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Wenzhong |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Yuanyuan |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Yiren |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Shi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Panpan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Lixin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhan, Qimin |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Nan |e verfasserin |4 aut | |
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