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Han D, Spengler BA, Ross RA. Increased wild-type N-ras activation by neurofibromin down-regulation increases human neuroblastoma stem cell malignancy. Genes Cancer. 2011;2(11):1034-43doi: 10.1177/1947601912443127.
Han, D., Spengler, B. A., & Ross, R. A. (2011). Increased wild-type N-ras activation by neurofibromin down-regulation increases human neuroblastoma stem cell malignancy. Genes & cancer, 2(11), 1034-43. https://doi.org/10.1177/1947601912443127
Han, Dan, et al. "Increased wild-type N-ras activation by neurofibromin down-regulation increases human neuroblastoma stem cell malignancy." Genes & cancer vol. 2,11 (2011): 1034-43. doi: https://doi.org/10.1177/1947601912443127
Han D, Spengler BA, Ross RA. Increased wild-type N-ras activation by neurofibromin down-regulation increases human neuroblastoma stem cell malignancy. Genes Cancer. 2011 Nov;2(11):1034-43. doi: 10.1177/1947601912443127. PMID: 22737269; PMCID: PMC3379567.
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Genes Cancer. 2011 Nov;2(11):1034-43. doi: 10.1177/1947601912443127.

Increased wild-type N-ras activation by neurofibromin down-regulation increases human neuroblastoma stem cell malignancy.

Genes & cancer

Dan Han, Barbara A Spengler, Robert A Ross

Affiliations

  1. Department of Biological Sciences, Fordham University, Bronx, NY, USA.

PMID: 22737269 PMCID: PMC3379567 DOI: 10.1177/1947601912443127

Abstract

Cellular heterogeneity is a well-known feature of human neuroblastoma tumors and cell lines. Of the 3 phenotypes (N-, I-, and S-type) isolated and characterized, the I-type cancer stem cell of neuroblastoma is the most malignant. Here, we report that, although wild-type N-Ras protein is expressed at the same level in all 3 neuroblastoma cell phenotypes, activated N-Ras-GTP level is significantly higher in I-type cancer stem cells. When activated N-Ras levels were decreased by transfection of a dominant-negative N-Ras construct, the malignant potential of I-type cancer stem cells decreased significantly. Conversely, when weakly malignant N-type cells were transfected with a constitutively active N-Ras construct, activated N-Ras levels, and malignant potential, were significantly increased. Thus, high levels of N-Ras-GTP are required for the increased malignancy of I-type neuroblastoma cancer stem cells. Moreover, increased activation of N-Ras results from significant down-regulation of neurofibromin (NF1), an important RasGAP. This specific down-regulation is mediated by an ubiquitin-proteasome-dependent pathway. Thus, decreased expression of NF1 in I-type neuroblastoma cancer stem cells causes a high level of activated N-Ras that is, at least in part, responsible for their higher tumorigenic potential.

Keywords: N-Ras; malignancy; neuroblastoma cancer stem cell; neurofibromin

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