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P14ARF deficiency and its correlation with overexpression of p53/MDM2 in sporadic vestibular schwannomas

  • Otology
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European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Recent studies have shed considerable light into schwannomas. To date, only merlin has been identified as a hallmark or pathogenesis of both sporadic and NF2-related schwannomas. Here, we show, by immunoblot and immunohistochemical analyses of 58 sporadic vestibular schwannomas, that upregulation of p53 was observed in 90 % of tumors examined. No p53 mutations were found in 12 % tumors analyzed. Expression of p14ARF was negative in 95 % of tumors, while overexpression of MDM2 was found in all specimens. Aberrant DNA hypermethylation of the p14ARF promoter was observed in three of seven tumors examined (43 %), associated with remarkably decreased mRNA levels. The very high degree of concordance in the aberrations of the p14ARF/MDM2/p53 pathway in this tumor may be considered to be a new player in the pathogenesis of sporadic vestibular schwannomas. Moreover, expression of p21 (waf1) was negative in all tumors, suggesting that the aberration of this pathway is associated with greater attenuation of p21-mediated signals that are critical for growth inhibition. These data are in agreement with the model in RT-4 rat schwannoma cells: i.e., overexpression of ARF was associated with accumulation of p21 expression both at protein and mRNA levels. ShRNA knock-down of p53 expression attenuated p21-mediated increase in cellular arrest in the G1-phase, suggesting that p14ARF regulates p21 protein levels through a p53-dependent pathway. Thus, this study reveals a high degree of concordance in the aberrations of the p14ARF/MDM2/p53 pathway with the development of sporadic vestibular schwannomas.

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Acknowledgments

This work was supported by the Grant 2009CB521703 from 973 Program of China to Hao Wu and the Natural Science Foundation of China (30801286 and 30973307) to Hao Wu.

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Otolaryngology, Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Kongjiang Road #1665, Shanghai, 200092, China

    Ying Chen, Zhao-yan Wang & Hao Wu

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  1. Ying Chen
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  2. Zhao-yan Wang
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  3. Hao Wu
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Correspondence to Hao Wu.

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Chen, Y., Wang, Zy. & Wu, H. P14ARF deficiency and its correlation with overexpression of p53/MDM2 in sporadic vestibular schwannomas. Eur Arch Otorhinolaryngol 272, 2227–2234 (2015). https://doi.org/10.1007/s00405-014-3135-y

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  • DOI: https://doi.org/10.1007/s00405-014-3135-y

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