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The neural guidance receptor Plexin C1 delays melanoma progression

Oncogene volume 32, pages 4941–4949 (2013)Cite this article

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Abstract

Plexin C1 is a type I transmembrane receptor with intrinsic R-Ras GTPase activity, which regulates cytoskeletal remodeling and adhesion in normal human melanocytes. Melanocytes are pigment-producing cells of the epidermis, precursors for melanoma, and express high levels of Plexin C1, which is lost in melanoma in vitro and in vivo. To determine if Plexin C1 is a tumor suppressor for melanoma, we introduced Plexin C1 into a primary human melanoma cell line, and phenotypes including migration, apoptosis, proliferation and tumor growth in mice were analyzed. Complimentary studies in which Plexin C1 was silenced in human melanocytes were performed. Plexin C1 significantly inhibited migration and proliferation in melanoma, whereas in melanocytes, loss of Plexin C1 increased migration and proliferation. In mouse xenografts, Plexin C1 delayed tumor growth of melanoma at early time points, but tumors eventually escaped the suppressive effects of Plexin C1, due to Plexin C1-dependent activation of the pro-survival protein Akt. R-Ras activation stimulates melanoma migration. Plexin C1 lowered R-Ras activity in melanoma and melanocytes, consistent with inhibitory effects of Plexin C1 on migration of melanocytes and melanoma. To determine if R-Ras is expressed in melanocytic lesions in vivo, staining of tissue microarrays of nevi and melanoma were performed. R-Ras expression was highly limited in melanocytic lesions, being essentially confined to primary melanoma, and almost completely absent in nevi and metastatic melanoma. These data suggest that loss of Plexin C1 in melanoma may promote early steps in melanoma progression through suppression of migration and proliferation, but pro-survival effects of Plexin C1 ultimately abrogate the tumor suppressive effects of Plexin C1. In primary melanoma, loss of Plexin C1 may function in early steps of melanoma progression by releasing inhibition of R-Ras activation, and stimulating migration.

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Abbreviations

SD:

standard deviation

Sema7A:

Semaphorin 7A

SEM:

standard error of the mean

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Acknowledgements

This work was supported in part by R01CA136499 (GS), by NIH training Grant 5T32AR007472 (JS), and by the Department of Biogenetics, University of Rochester (LX). We also thank Lori Moll (Oncogene Inc.,) for assistance with subcloning of Plexin C1.

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Authors and Affiliations

  1. Department of Dermatology, University of Rochester School of Medicine, Rochester, NY, USA

    Y Chen, J Soong & G Scott

  2. Department of Pathology, University of Rochester School of Medicine, Rochester, NY, USA

    J Soong & G Scott

  3. Department of Biomedical Genetics, University of Rochester School of Medicine, Rochester, NY, USA

    S Mohanty & L Xu

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  1. Y Chen
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Correspondence to G Scott.

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Chen, Y., Soong, J., Mohanty, S. et al. The neural guidance receptor Plexin C1 delays melanoma progression. Oncogene 32, 4941–4949 (2013). https://doi.org/10.1038/onc.2012.511

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