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LINC00460 promotes neuroblastoma tumorigenesis and cisplatin resistance by targeting miR-149-5p/DLL1 axis and activating Notch pathway in vitro and in vivo

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Abstract

Long noncoding RNAs (lncRNAs) have been demonstrated to participate in neuroblastoma cisplatin resistance and tumorigenesis. LncRNA LINC00460 was previously reported to play a critical regulatory role in many cancer development. Nevertheless, its role in modulating neuroblastoma cisplatin resistance has not been explored till now. Cisplatin-resistant neuroblastoma cell lines were established by exposing neuroblastoma cell lines to progressively increasing concentrations of cisplatin for 6 months. LINC00460, microRNA (miR)-149-5p, and delta-like ligand 1 (DLL1) mRNA expression was measured through RT-qPCR. The protein levels of DLL1, epithelial-to-mesenchymal transition (EMT) markers, and the Notch signaling-related molecules were measured via western blotting. The IC50 value for cisplatin, cell growth, metastasis and apoptosis were analyzed in cisplatin-resistant neuroblastoma cells. The binding between LINC00460 (or DLL1) and miR-149-5p was validated through dual-luciferase reporter assay. The murine xenograft model was established to perform in vivo assays. LINC00460 and DLL1 levels were elevated, while miR-149-5p level was reduced in cisplatin-resistant neuroblastoma cells. LINC00460 depletion attenuated IC50 values for cisplatin, weakened cell growth, metastasis, and EMT, and enhanced apoptosis in cisplatin-resistant neuroblastoma cells. Mechanically, LINC00460 sponged miR-338-3p to increase DLL1 level, thereby activating Notch signaling pathway. DLL1 overexpression antagonized LINC00460 silencing-induced suppression on neuroblastoma cell cisplatin resistance and malignant behaviors, while such effects were further reversed by treatment with DAPT, the inhibitor of Notch pathway. Additionally, LINC00460 knockdown further augmented cisplatin-induced impairment on tumor growth in vivo. LINC00460 contributes to neuroblastoma cisplatin resistance and tumorigenesis through miR-149-5p/DLL1/Notch pathway, providing new directions to improve the therapeutic efficacy of chemotherapy drugs applied in patients with neuroblastoma.

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Availability of data and materials

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

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Funding

This work was supported by The Joint Fund Project of Science and Technology Innovation in Fujian Province (2021Y9118).

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  1. Yali Xu and Zhixin Qiu contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Surgery, The First Affiliated Hospital of Fujian Medical University, 20 Cha-Zhong Road, Taijiang District, Fuzhou, 350005, China

    Yali Xu, Zhixin Qiu, Jinwen Chen & Junshan Lin

  2. The First Clinical Medical School, Fujian Medical University, Fuzhou, 350005, China

    Lihong Huang & Jiaqi Zhang

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Contributions

Yali Xu and Zhixin Qiu conceived and designed the experiments. Yali Xu, Zhixin Qiu, Jinwen Chen, Lihong Huang, Jiaqi Zhang and Junshan Lin carried out the experiments. Yali Xu, Zhixin Qiu and Junshan Lin analyzed the data. Yali Xu, Zhixin Qiu and Junshan Lin drafted the manuscript. All authors agreed to be accountable for all aspects of the work. All authors have read and approved the final manuscript.

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Correspondence to Junshan Lin.

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Human tissue study was approved by the Ethics Committee of The First Affiliated Hospital of Fujian Medical University (Approval number: MRCTA,ECFAH of FMU[2022]318). The Institutional Animal Care and Use Committee of Hubei Provincial Center for Disease Control and Prevention authorized the animal experiments (Approval number: 202310037).

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Xu, Y., Qiu, Z., Chen, J. et al. LINC00460 promotes neuroblastoma tumorigenesis and cisplatin resistance by targeting miR-149-5p/DLL1 axis and activating Notch pathway in vitro and in vivo. Drug Deliv. and Transl. Res. 14, 2003–2018 (2024). https://doi.org/10.1007/s13346-023-01505-6

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