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BRCA1-associated protein inhibits glioma cell proliferation and migration and glioma stem cell self-renewal via the TGF-β/PI3K/AKT/mTOR signalling pathway

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Abstract

Purpose

BRCA1-associated protein (BRAP) was first identified by its ability to bind to the nuclear localization signalling motif of BRCA1 and other proteins. Subsequently, human BRAP has been found to exert multiple functions, many of which are related to cancer development. Up till now, however, the role of BRAP in glioma development has remained obscure. Here, we report a role for BRAP in mediating the proliferation and migration of glioma cells both in vitro and in vivo.

Methods

The expression of BRAP in 98 glioma patient samples was determined by immunohistochemistry, after which associations between BRAP expression and patient prognosis were assessed. A short hairpin RNA (shRNA) was used to knock down BRAP and an expression vector was used to exogenously overexpress BRAP in glioma cells. The effects of BRAP expression on tumour cell behaviour in vitro and in an in vivo xenograft mouse model were examined.

Results

We found that in glioma patients BRAP expression was associated with a favourable prognosis. We also found that shRNA-mediated knockdown of BRAP facilitated the proliferation and migration of glioma cells and the self-renewal of glioma stem cells. In parallel, we found that BRAP knockdown increased tumour growth and invasion and decreased survival in an in vivo glioma xenograft mouse model. Mechanistically, we found that BRAP inhibited glioma cell proliferation and migration, as well as glioma stem cell self-renewal via the TGF-β/PI3K/AKT/mTOR signalling pathway.

Conclusions

Together, our findings identify BRAP as a mediator of glioma cell proliferation, migration and glioma stem cell self-renewal.

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Funding

This work was supported by an Open Project of the State Key Laboratory of Medicinal Chemical Biology, Nankai University [grant number 2018048], Fundamental Research Funds for the Central Universities, Nankai University [grant number 63191106], the Chinese National Natural Science Foundation [grant number 81671380, 81902477], Key Project of Tianjin National Natural Science Foundation [grant number 17JCZDJC35900], the Science and Technology Development Foundation of Henan Province [172102310103], Henan Provincial Medical Science and Technology Project [grant number 2018020480] and the Chinese National Natural Science Foundation [grant number 81573737].

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Author notes

  1. Bo Wang, Chen Cao and Xi Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Tianjin Huanhu Hospital; Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, No. 6 Jizhao Road, Tianjin, 300350, China

    Bo Wang & Budong Chen

  2. State Key Laboratory of Medicinal Chemical Biology, Nankai University, No.94 Weijin Road, Tianjin, 300071, China

    Bo Wang

  3. Department of Medical Imaging, Tianjin Huanhu Hospital; Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, No. 6 Jizhao Road, Tianjin, 300350, China

    Chen Cao

  4. Department of Gastroenterology, Tianjin Nankai Hospital, No.6 Changjiang Road, Tianjin, 300100, China

    Xi Liu

  5. Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA

    Xin He

  6. Department of Hepatic Biliary Pancreatic Surgery, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou, 450008, Henan Province, China

    Hao Zhuang

  7. Department of Neurosurgery, General Hospital; Tianjin Key Laboratory of Injuries, Variations, and Regeneration of Nervous System; Tianjin Neurological Institute, Tianjin Medical University, No.154 Anshan Road, Tianjin, 300052, China

    Dong Wang

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Correspondence to Hao Zhuang, Dong Wang or Budong Chen.

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Ethics approval and consent to participate

All subjects provided written informed consent before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Tianjin Huanhu Hospital (NO.2019–14). All human tissue samples were obtained with patient consent. Animal experiments were performed according to the Health guidelines of the Tianjin Huanhu Hospital Animal Use and Care Committee.

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Wang, B., Cao, C., Liu, X. et al. BRCA1-associated protein inhibits glioma cell proliferation and migration and glioma stem cell self-renewal via the TGF-β/PI3K/AKT/mTOR signalling pathway. Cell Oncol. 43, 223–235 (2020). https://doi.org/10.1007/s13402-019-00482-8

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