Identification of RECK as an evolutionarily conserved tumor suppressor gene for zebrafish malignant peripheral nerve sheath tumors
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Rashmi Kumari1,*, Martin R. Silic1,*, Yava L. Jones-Hall1,2, Alexandra Nin-Velez1, Jer-Yen Yang3,4,5, Suresh K. Mittal1,2,4 and GuangJun Zhang1,2,4,5
1Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47907, USA
2Purdue Institute for Inflammation, Immunology and Infectious Disease (PI4D), Purdue University, West Lafayette, Indiana 47907, USA
3Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana 47907, USA
4Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA
5Purude Institute for Integrative Neuroscience, Purdue University, West Lafayette, Indiana 47907, USA
*These authors contributed equally to this work
GuangJun Zhang, email: [email protected]
Keywords: RECK; tumor suppressor gene (TSG); MPNST; pPNET; zebrafish
Abbreviations: MPNST: malignant peripheral nerve sheath tumor; pPNET: peripheral primitive neuro-ectodermal tumor; TSG: tumor suppressor gene; CNAs: copy number alterations; LOH: loss of heterozygosity
Received: May 16, 2017 Accepted: April 08, 2018 Published: May 04, 2018
Malignant peripheral nerve sheath tumors (MPNSTs) are a type of sarcoma with poor prognosis due to their complex genetic changes, invasive growth, and insensitivity to chemo- and radiotherapies. One of the most frequently lost chromosome arms in human MPNSTs is chromosome 9p. However, the cancer driver genes located on it remain largely unknown, except the tumor suppressor gene, p16 (INK4)/CDKN2A. Previously, we identified RECK as a tumor suppressor gene candidate on chromosome 9p using zebrafish-human comparative oncogenomics. In this study, we investigated the tumorigenesis of the reck gene using zebrafish genetic models in both tp53 and ribosomal protein gene mutation background. We also examined the biological effects of RECK gene restoration in human MPNST cell lines. These results provide the first genetic evidence that reck is a bona fide tumor suppressor gene for MPNSTs in zebrafish. In addition, restoration of the RECK gene in human MPNST cells leads to growth inhibition suggesting that the reactivation of RECK could serve as a potential therapeutic strategy for MPNSTs.
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