Abstract
Adult stem cells are multipotent and persist in small numbers in adult tissues throughout the lifespan of an organism. Unlike differentiated cells, adult stem cells are intrinsically resistant to senescence. It is unclear how adult stem cells in solid organs respond to oncogenic stimulation and whether these cells have a role in tumor initiation. We report here that expression of BRAFV600E in human neural crest progenitor cells (hNCPCs) did not induce growth arrest as seen in human melanocytes, but instead, increased their cell proliferation capacity. These cells (hNCPCsV600E) acquired anchorage-independent growth ability and were weakly tumorigenic in vivo. Unlike in human melanocytes, BRAFV600E expression in hNCPCs did not induce p16INK4a expression. BRAFV600E induced elevated expression of CDK2, CDK4, MITF and EST1/2 protein in hNCPCs, and also induced melanocytic differentiation of these cells. Furthermore, overexpression of MITF in hNCPCsV600E dramatically increased their tumorigenicity and resulted in fully transformed tumor cells. These findings indicate that hNCPCs are susceptible to BRAFV600E-induced transformation, and MITF potentiates the oncogenic effect of BRAFV600E in these progenitor cells. These results suggest that the hNCPCs are potential targets for BRAFV600E-induced melanocytic tumor formation.
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Acknowledgements
We thank Drs M Herlyn from the Wistar Institute, Philadelphia, PA for melanoma cell lines, R Marais from the Institute of Cancer Research, London, UK for BRAFV600E plasmids, S Carreira from Marie Curie Research Institute, UK for MITF promoter-luciferase plasmids, F Liu from university of California for QCXIP-MiTF and QCXIP vectors, K Huang for editing the manuscript. CHTN for providing tissues and the immunohistochemical lab at the Department of Pathology and Laboratory medicine, University of Pennsylvania for immunohistochemical stains. This work is supported by US National Institutes of Health grants AR-054593, CA-116103 to XX.
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Kumar, S., Dai, J., Li, S. et al. Human skin neural crest progenitor cells are susceptible to BRAFV600E-induced transformation. Oncogene 33, 832–841 (2014). https://doi.org/10.1038/onc.2012.642
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DOI: https://doi.org/10.1038/onc.2012.642
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