Identification of RECK as an evolutionarily conserved tumor suppressor gene for zebrafish malignant peripheral nerve sheath tumors.

Rashmi Kumari,Suresh K Mittal,Yava L Jones-Hall,Guangjun Zhang,Alexandra Nin-Velez,Jer-Yen Yang,Martin R Silic

doi:10.18632/oncotarget.25236

Abstract

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.

Highlights

Malignant peripheral nerve sheath tumors (MPNSTs) are a type of sarcoma that originate from the neural crest/Schwann cell lineage in humans, and have a poor prognosis due to their complex genetic changes, invasive growth nature, and insensitiveness to chemo- and radiotherapies [1,2,3]
Accumulating evidence from cellular experiments indicates that the RECK gene is a tumor suppressor gene (TSG) in vivo, there is no clear genetic evidence to prove this notion, since this gene is a developmentally essential gene in mouse [26, 31]
We validate that the restoration of RECK leads to inhibition of human MPNST cell growth

Summary

Introduction

Malignant peripheral nerve sheath tumors (MPNSTs) are a type of sarcoma that originate from the neural crest/Schwann cell lineage in humans, and have a poor prognosis due to their complex genetic changes, invasive growth nature, and insensitiveness to chemo- and radiotherapies [1,2,3]. For the etiology of MPNST, only a few cancer genes are currently known to be related to this type of malignancy: NF1, NF2, SMARCB1 and LZTR1. There is currently no targeted therapy available for this type of malignancy, mainly due to the lack of knowledge of its cancer driver genes. Cancer driver genes are a small number of genes found mutated in cancer genomes, and their mutations biologically contribute to cancer initiation and progression [7]. One of the goals of current cancer research is to identify all the cancer driver genes, so that they can be pursued as new targets for the development of cancer therapy. Targeted cancer therapy has emerged as a better alternative to other treatment options because of its high specificity and fewer side effects. Effective targeted cancer therapies require accurate identification of the targetable cancer driver genes

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Results

Conclusion