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Role of VHL-JAK-STAT signaling pathway in central nervous system hemangioblastoma associated with von Hippel-Lindau disease

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Abstract

Introduction

Central nervous system hemangioblastoma is a benign tumor associated with or without von Hippel-Lindau (VHL) disease which is an autosomal dominant hereditary disease that results from a germline mutation in the VHL gene. A main axis of signaling pathways in central nervous system hemangioblastoma is VHL-HIF signaling pathway. Here, we propose an alternative VHL-JAK-STAT signaling pathway in hemangioblastoma and discuss the role.

Methods

Using MACS method, Scl+ hemangioblast-like cells were isolated from multipotent nestin-expressing stem cells. Then, ubiquitination of JAK2 in those cells and immunoprecipitation between JAK2 and VHL were examined. Then, expressions of JAK2 and STAT3 in those cells and expressions of VHL-associated hemangioblastoma tissues were examined. In addition, the VHL genes of patients bearing hemangioblastoma were analyzed.

Results

JAK2 and STAT3 in Scl+ hemangioblast-like cells were ubiquitinated after VHL- expression vector was transferred to those cells. Expressions of JAK2 and STAT3 in those cells were well recognized before the transfer, but those disappeared after the transfer. Expressions of both JAK2 and STAT3 in hemangioblastoma tissues were well shown. The VHL gene analysis revealed that patients bearing hemangioblastoma carried missense mutations in 5, small deletions in 2, large deletions in 4, and nonsense mutation in 1

Conclusions

VHL-JAK-STAT signaling pathway might play an important role in proliferation, angiogenesis, and maintenance of stem-cell-nature in hemangioblastoma as an alternative signaling pathway to supplement VHL-HIF signaling pathway.

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Authors and Affiliations

  1. Department of Neurosurgery, International University of Health and Welfare Atami Hospital, 13-1 Higashikaigan-cho, Atami, Shizuoka, 413-0012, Japan

    Hiroshi Kanno, Tetsuya Yoshizumi & Masamichi Shinonaga

  2. Department of Neurosurgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan

    Atsuhiko Kubo & Hidetoshi Murata

  3. Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan

    Masahiro Yao

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  1. Hiroshi Kanno
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  2. Tetsuya Yoshizumi
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  3. Masamichi Shinonaga
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  4. Atsuhiko Kubo
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  5. Hidetoshi Murata
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Contributions

Conception and design: HK; Acquisition of data: HK, TY, HM, MS, AK, MY; Analysis and interpretation of data: HK, TY, AK, MY; Drafting the article: HK; Reviewed submitted version of manuscript: HK; Approved the final version of the manuscript on behalf of all authors: HK; Administrative/technical/material support: HK, TY, MS, MY; Study supervision: HK, MY.

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Correspondence to Hiroshi Kanno.

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Written informed patient consent was obtained for studying germline analysis and protein expression profiles, and the study protocol was approved by the institutional ethics committee.

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Kanno, H., Yoshizumi, T., Shinonaga, M. et al. Role of VHL-JAK-STAT signaling pathway in central nervous system hemangioblastoma associated with von Hippel-Lindau disease. J Neurooncol 148, 29–38 (2020). https://doi.org/10.1007/s11060-020-03506-8

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  • DOI: https://doi.org/10.1007/s11060-020-03506-8

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