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A microprotein encoded by LINC00263 promotes breast cancer osteolytic bone metastasis by inducing osteoclastogenesis and inhibiting osteoclast ferroptosis

Oncogene volume 44, pages 2201–2216 (2025)Cite this article

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Abstract

Currently, there are no effective prevention or therapeutic methods for breast cancer bone metastasis (BC-BM), which leading to severe skeletal complications and increased mortality. Understanding the mechanisms underlying BC-BM could provide potential strategies for its prevention and treatment. In this study, we identified a new microprotein encoded by lncRNA LINC00263, which we named LINC00263-encoded protein (LINC00263-P), was significantly upregulated in bone metastatic breast cancer tissues and correlated with BC-BM. Overexpression of LINC00263 significantly promoted BC-BM, while treatment with the neutralizing anti-LINC00263-P antibody effectively inhibited BC-BM. Mechanically, the LINC00263-P binds to integrin αvβ3 for activating Src/Syk/Vav-3 axis and yes-associated protein 1 (YAP1) pathway, which enhanced osteoclastogenesis and diminishes ferroptosis in osteoclasts, thereby creating an osteolytic bone metastasis niche that fosters BC-BM. Importantly, treatment with angoroside C, an active component from the traditional Chinese medicine Scrophulariae Radix extract, effectively blocked the binding of LINC00263-P to αvβ3, thereby inhibiting abnormal osteoclastogenesis and preventing BC-BM. These findings highlight the crucial role of microprotein LINC00263-P in disrupting bone homeostasis and propose a potential molecular mechanism of BC-BM.

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Fig. 1: LINC00263-P is significantly upregulated in breast cancer with bone metastasis.
Fig. 2: LINC00263-P promote osteolytic bone metastasis in breast cancer.
Fig. 3: LINC00263-P promotes osteoclastogenesis.
Fig. 4: LINC00263-P inhibits osteoclasts ferroptosis.
Fig. 5: LINC00263-P promotes podosome formation and inhibits osteoclasts ferroptosis by interacting with αvβ3.
Fig. 6: LINC00263-P inhibits osteoclasts ferroptosis by activating αvβ3.
Fig. 7: Angoroside C inhibits the interaction between LINC00263-P and integrin αvβ3.
Fig. 8: Angoroside C treatment inhibits osteoclastogenesis and BC-BM.

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Data availability

All datasets have been deposited and made publicly available: the quantitative proteomics mass-spectrometry data on protein from MDA-MB-231 and SCP2 cells that support the findings of this study have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD059452; the RNA sequencing data have been deposited in the NCBI Sequence Read Archive (SRA) under the BioProject Accession No. PRJNA1206327. The datasets used and/or analysis during the current study are available from the corresponding author on reasonable request.

Change history

  • 09 May 2025

    Affiliation 2, Department of Oncology, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China, has been moved to 1st affiliation.

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Acknowledgements

This work was supported by the Guangdong Basic and Applied Basic Research Foundation (no.2022A1515111204 and 2023A1515110051), Natural Science Foundation of China (no. 82303401, 82330082 and 82030078), the Fundamental Research Funds for Shenzhen Medical Research Fund (B2302046) and Guangzhou Municipal Science and Technology Project (2024A04J3475 and 2025A03J3756). We would like to thank Prof. Guohong Hu of the Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine for kindly providing the SCP2 cell lines.

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  1. These authors contributed equally: Suwen Chen, Miaoling Tang.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

    Suwen Chen, Miaoling Tang & Jun Li

  2. Department of Oncobiology, Department of Basic Medical Sciences, Shantou University Medical College, Shantou, Guangdong, China

    Suwen Chen, Miaoling Tang & Shuxia Zhang

  3. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

    Suwen Chen, Xuexin Yu, Wanying Qian & Jun Li

  4. Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

    Yingru Xu

  5. Biomedicine Research Centre, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provicial Clinical Research Center for Obsterics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China

    Geyan Wu

  6. The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Cancer Research Center, Shantou University Medical College, Shantou, Guangdong, China

    Shuxia Zhang

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Contributions

SXZ: funding acquisition, project administration, manuscript review and editing; GYW: funding acquisition, experimental design, study supervision; SWC: writing original draft, data analysis; MLT: performing the experiments, data analysis; XXY: provision of patient tissue samples, clinical data analysis; WYQ: mice experiments; YRX: funding acquisition, experimental assistance; JL: funding acquisition.

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Correspondence to Geyan Wu or Shuxia Zhang.

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All methods were performed in accordance with the relevant guidelines and regulation. All animal procedures were approved by the Sun Yat-sen University Institutional Animal Care and Use Committee (Approval No. SYSU-IACUC-2022-001151). And the research involving human tissues was approved by the Clinical Research of the First Affiliated Hospital of Sun Yat-sen University Ethical Committee. All patient samples were collected in accordance with the Declaration of Helsinki, with written informed consent obtained from all participants.

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Chen, S., Tang, M., Yu, X. et al. A microprotein encoded by LINC00263 promotes breast cancer osteolytic bone metastasis by inducing osteoclastogenesis and inhibiting osteoclast ferroptosis. Oncogene 44, 2201–2216 (2025). https://doi.org/10.1038/s41388-025-03400-5

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