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PLK3 promotes the proneural–mesenchymal transition in glioblastoma via transcriptional regulation of C5AR1

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Abstract

Background

Accumulating evidence suggests that polo-like kinase 3 (PLK3) plays an essential role in tumor cells and induces cell proliferation and may have implications for the prognosis of various cancers. We sought to define the role of PLK3-dependent proneural–mesenchymal transition (PMT) in the glioblastoma (GBM) therapy.

Methods and results

We analyzed the expression data for PLK3 by using the TCGA database. PLK3 expression in GBM cell lines was determined by qRT-PCR and Western blotting. PLK3 levels were modulated using Lentivirus infection, and the effects on symptoms, tumor volume, and survival in mice intracranial xenograft models were determined. Irradiation (IR) was performed to induce PMT. PLK3 expression was significantly elevated in mesenchymal subtype GBM and promoted tumor proliferation in GBM. Additionally enriched PLK3 expression could be associated with poor prognosis in GBM patients compared with those who have lower PLK3 expression. Mechanically, PLK3-dependent PMT induced radioresistance in GBM cells via transcriptional regulation of complement C5a receptor 1 (C5AR1). In therapeutic experiments conducted in vitro, targeting PLK3 by using small molecule inhibitor decreased tumor growth and radioresistance of GBM cells both in vitro and in vivo.

Conclusions

PLK3-C5AR1 axis induced PMT thus enhanced radioresistance in GBM and could become a novel potential therapeutic target for GBM.

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Acknowledgements

This study was supported by the Exploration and Innovation Project of First Affiliated Hospital of Xi'an Jiaotong University (No. 2022MS-15); Shaanxi Provincial Key Research and Development Program (No. 2021KW-51); Natural Science Basic Research Plan in Shaanxi Province of China (No. 2022JQ-791); and Special Fund for Personnel Training of Second Affiliated Hospital of Xi'an Jiaotong University (No. RC(XM)202007).

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Author notes

  1. Shuo Yu and Lin Lv have equally contributed to this work.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta West Road, Xi’an, 710000, Shaanxi, China

    Shuo Yu, Lin Lv, Yang Li, Qian Ning, Tingting Liu & Tinghua Hu

  2. Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710000, Shaanxi, China

    Shuo Yu

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  1. Shuo Yu
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Contributions

All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by LL, YL, QN, and TH. The first draft of the manuscript was written by SY and all authors commented on the previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Tinghua Hu.

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Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

This study was performed in line with the principles of the declaration of Helsinki, and all experimental procedures followed the guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Approval was granted by the Ethics Committee of the first affiliated hospital of Xi'an Jiaotong University (Approval Number: 2021-695).

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Yu, S., Lv, L., Li, Y. et al. PLK3 promotes the proneural–mesenchymal transition in glioblastoma via transcriptional regulation of C5AR1. Mol Biol Rep 50, 8249–8258 (2023). https://doi.org/10.1007/s11033-023-08716-7

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