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Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth

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Abstract

Purpose

Glioma is a highly aggressive and lethal brain tumor. Signal transducers and activators of transcription (STAT) pathway are widely implicated in glioma carcinogenesis. Our previous study found that the Fynrelated kinase (FRK) gene, plays as a tumor suppressor in the development and progression of glioma. This study aimed to investigate the role of FRK in the activation pathway of STATs and its effect on the growth of glioma.

Methods

The U251 and U87 cells with stable FRK overexpression were generated by lentivirus technique. The effects of FRK on the related proteins of STAT signaling pathway were detected by western blotting. Coimmunoprecipitation was used to detect the association of FRK and STAT1. The effects of STAT1 on the proliferation of glioma cells were detected by CCK8 or Edu cell proliferation assays. The expressions and correlation of FRK and p-STAT1 in glioma tissues were detectd by western blotting or immunohistochemistry. The effect of FRK on the growth of glioma was investigated in vivo mouse model.

Results

The level of p-JAK2 and p-STAT1 increased after FRK overexpression, while they decreased after FRK downregulation both in U251 and U87 cells. However, FRK had no effect on STAT3 phosphorylation. FRK-induced STAT1 activation was not dependent on JAK2. FRK associated with STAT1, induced STAT1 nuclear translocation and regulated the expressions of STAT1-related target genes. STAT1 overexpression suppressed the proliferation of glioma cells. In contrast, STAT1 knockdown by siRNA promoted glioma cell growth. Importantly, down-regulation of STAT1 partially attenuated FRK-induced growth suppression. The clinical sample-based study indicated that the expression of FRK was significantly correlated with the expression of p-STAT1. FRK significantly inhibited glioma tumor growth in vivo.

Conclusions

Our findings highlighted a critical role of FRK in tumor suppression ability through promoting STAT1 activation, and provided a potential therapeutic target for glioma.

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Acknowledgements

This work was financially supported by National Natural Science Foundation of China (Grants Nos. 81302175, 8170110153), Natural Science Foundation of Jiangsu Province (Grants No. BK20181152), Jiangsu Provincial Medical Youth Talent (No. QNRC2016786), The Medical scientific research project of Jiangsu Health and Health Committee (H2018015), Xuzhou Municipal Bureau of Science and Technology (Nos. KC18146, KC17095).

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Author notes

  1. Lei Hua, Guanghui Wang and Zhen Wang contributed equally to this work.

Authors and Affiliations

  1. Nanjing Medical University, Nanjing, 211166, Jiangsu, People’s Republic of China

    Lei Hua & Rutong Yu

  2. Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, People’s Republic of China

    Lei Hua, Jiale Fu, Hongmei Liu & Rutong Yu

  3. Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu, People’s Republic of China

    Lei Hua, Liang Zhao, Zhenkun Zong, Chengkun Ye, Hongmei Liu, Yufu Zhu & Rutong Yu

  4. Department of Gynaecology and Obstetrics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, Jiangsu, People’s Republic of China

    Guanghui Wang

  5. Department of Neurosurgery, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, 210000, Jiangsu, People’s Republic of China

    Zhen Wang

  6. Department of Neurosurgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu, People’s Republic of China

    Zhen Fang

  7. Henan Key Laboratory of immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, 453003, Henan, People’s Republic of China

    Ting Zhuang

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  1. Lei Hua
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Correspondence to Hongmei Liu, Yufu Zhu or Rutong Yu.

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This article contains studies with human participants performed by authors and all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article contains studies with animals performed by authors and all applicable international, national, and/or institutional guidelines for the care and use of animals were followed. Informed consent was obtained from all individual participants included in the study.

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Hua, L., Wang, G., Wang, Z. et al. Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth. J Neurooncol 143, 35–47 (2019). https://doi.org/10.1007/s11060-019-03143-w

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