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Midkine promotes breast cancer cell proliferation and migration by upregulating NR3C1 expression and activating the NF-κB pathway

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Abstract

Background

Breast cancer (BC) is the most common malignancy in females and is the second leading cause of cancer-related death among women worldwide. Midkine (MDK) is a heparin-binding growth factor that is abnormally expressed at high levels in various human malignancies. We aimed to uncover the biological function and molecular mechanism of MDK in BC cells.

Methods and results

MDA-MB-231-shMDK and T47D-shMDK BC cells were established. The in vitro biological functions of MDK were demonstrated by CCK-8 assays, Transwell assays and Western blotting, whereas qPCR pathway arrays were implemented to explore the mechanism of MDK in BC cells. Functionally, we verified that silencing MDK significantly suppressed BC cell proliferation and migration by inhibiting the activation of the nuclear factor kappa B (NF-κB) pathway and the nuclear distribution of NF-κB. Meanwhile, Ingenuity Pathway Analysis (IPA) and a qPCR pathway array revealed that silencing MDK decreased the expression of NR3C1, a potential downstream target of the NF-κB pathway. We also confirmed that treatment with an NF-κB inhibitor suppressed NR3C1 expression in BC cells. Finally, we demonstrated that silencing NR3C1 repressed BC cell proliferation and migration.

Conclusions

Our findings highlight a novel mechanism by which MDK influences BC progression via regulation of the NF-κB-NR3C1 pathway.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82002919), Jiangsu Province Key Laboratory of Immunity and Metabolism Open Project Fund (JSKIM201803), Xuzhou Science and Technology Project (KC20101, KC20070) and Jiangsu Province Key Laboratory of Anesthesiology Open Project Fund (XZSYSKF2019023).

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Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Lin Zhang, Peng Zhang & Qingling Wang

  2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Lin Zhang

  3. Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China

    Lin Zhang, Li Song, Yanyan Xu, Yuting Xu, Maojin Zheng & Qingling Wang

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  1. Lin Zhang
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Contributions

LZ and QW proposed the hypotheses and designed the research; LZ, YX performed the experiments; YX and PZ participated in the analysis of the results; LS and MZ edited the pictures; LS revised the manuscript; QW supervised research and Finalize the final draft.

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Correspondence to Qingling Wang.

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Zhang, L., Song, L., Xu, Y. et al. Midkine promotes breast cancer cell proliferation and migration by upregulating NR3C1 expression and activating the NF-κB pathway. Mol Biol Rep 49, 2953–2961 (2022). https://doi.org/10.1007/s11033-022-07116-7

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  • DOI: https://doi.org/10.1007/s11033-022-07116-7

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