Long non-coding RNA NORAD serves as a promoter of oncogenesis and inhibits ferroptosis via miR-144-3p-mTOR-ferritinophagy axis in cancer
Abstract Non-coding RNA activated by DNA damage (NORAD) has been found to enhance proliferation and metastasis of cancer cells. Ferroptosis is characterized by excess lipid peroxidation and has been confirmed to eliminate cancer cells. However, the specific role of NORAD in cancer and ferroptosis is...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-08-01
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| Series: | European Journal of Medical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40001-025-02998-2 |
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| Summary: | Abstract Non-coding RNA activated by DNA damage (NORAD) has been found to enhance proliferation and metastasis of cancer cells. Ferroptosis is characterized by excess lipid peroxidation and has been confirmed to eliminate cancer cells. However, the specific role of NORAD in cancer and ferroptosis is not clear. In this study, data from public databases were downloaded to investigate role of NORAD in cancer. NORAD expression was higher in cancer tissues than in normal and was positively related with worse survival of patients. NORAD was negatively related with effect of multiple anti-cancer agents. Epigenetic factors, including lower DNA methylation and EP300-induced higher histone acetylation resulted in enhanced expression of NORAD. GO and KEGG analysis showed that NORAD participated in lipid peroxidation and ROS metabolism, indicating that NORAD may serve as a role in ferroptosis. Indeed, in-vitro and in-vivo assays showed that expression of NORAD is negatively related with ferroptosis in cancer cells. Mechanically, NORAD competitively bound with miR-144-3p and resulted in up-regulation of mTOR which served as an inhibitor of ferritinophagy. Decreased ferritinophagy led to lower free iron ions and the following reduced ferroptosis. Inhibited ferroptosis by NORAD was expanded by autophagy inhibitor 3-MA and reversed by autophagy inducer EBSS. Lastly, application of anti-cancer treatment cisplatin, radiation, doxorubicin and PTX exhibited synergetic anti-cancer effect with NORAD knock-down, and NORAD over-expression attenuated anti-cancer effect of drugs. In total, NORAD is a promoter of oncogenesis and inhibited ferroptosis via miR-144-3p-mTOR-ferritinophagy in cancer cells. Graphical Abstract |
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| ISSN: | 2047-783X |