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MicroRNA-98 Attenuates Cell Migration and Invasion in Glioma by Directly Targeting Pre-B Cell Leukemia Homeobox 3

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Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The extraordinary invasion of human GBM into adjacent normal brain tissues contributes to treatment failure. However, the mechanisms that control this process remain poorly understood. Increasing evidence has demonstrated that microRNAs are strongly implicated in the migration and invasion of GBM. In this study, we found that microRNA-98 (miR-98) was markedly downregulated in human glioma tissues and cell lines. Functional experiments indicated that restored expression of miR-98 attenuated glioma cell invasion and migration, whereas depletion of miR-98 promoted glioma cell invasion and migration. Subsequent investigation showed that pre-B-cell leukemia homeobox 3 (PBX3), an important transcription factor that controls tumor invasion, was a direct and functional target of miR-98 in GBM cells. Consistently, an orthotopic mouse model also demonstrated the suppressive effects of miR-98 overexpression on tumor invasion and PBX3 expression. Silencing of PBX3 using small interfering RNA inhibited the migratory and invasive capacities of glioma cells, whereas reintroduction of PBX3 into glioma cells reversed the anti-invasive function of miR-98. Furthermore, depletion of PBX3 phenocopied the effects of miR-98 overexpression in vivo. Finally, quantitative real-time polymerase chain reaction results showed that miR-98 was negatively correlated with PBX3 expression in 24 glioma tissues. Thus, we propose that PBX3 modulation by miR-98 has an important role in regulating GBM invasion and may serve as therapeutic target for GBM.

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Acknowledgements

This work was funded by the National Natural Science Foundation of China (81300998 and 81471269), National Natural Science Foundation of Jiangsu Province (BK20131022 and BK20160047), Jiangsu Province's Key Discipline of Medicine (XK201117), Jiangsu Province and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Specially Appointed Professor Foundation of Jiangsu Province (ky216r201307).

Author contributions

Xiupeng Xu and Zhongyuan Bao wrote the manuscript. Xiupeng Xu and Zhongyuan Bao performed and analyzed experiments and prepared the figures. Yinlong Liu and Jing Ji conceived experiments. Ning Liu and Jing Ji assisted with data analysis. All authors reviewed the manuscript.

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    1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

      Xiupeng Xu, Zhongyuan Bao, Yinlong Liu, Jing Ji & Ning Liu

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    1. Xiupeng Xu
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    Correspondence to Jing Ji or Ning Liu.

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    Xiupeng Xu and Zhongyuan Bao contributed equally to this work.

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    Xu, X., Bao, Z., Liu, Y. et al. MicroRNA-98 Attenuates Cell Migration and Invasion in Glioma by Directly Targeting Pre-B Cell Leukemia Homeobox 3. Cell Mol Neurobiol 37, 1359–1371 (2017). https://doi.org/10.1007/s10571-017-0466-4

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