Distinct role of ShcC docking protein in the differentiation of neuroblastoma.
The biological and clinical heterogeneity of neuroblastoma is closely associated with signaling pathways that control cellular characteristics such as proliferation, survival and differentiation. The Shc family of docking proteins is important in these pathways by mediating cellular signaling. In this study, we analysed the expression levels of ShcA and ShcC proteins in 46 neuroblastoma samples and showed that a significantly higher level of ShcC protein is observed in neuroblastomas with poor prognostic factors such as advanced stage and MYCN amplification (P<0.005), whereas the expression level of ShcA showed no significant association with these factors. Using TNB1 cells that express a high level of ShcC protein, it was demonstrated that knockdown of ShcC by RNAi caused elevation in the phosphorylation of ShcA, which resulted in sustained extracellular signal-regulated kinase activation and neurite outgrowth. The neurites induced by ShcC knockdown expressed several markers of neuronal differentiation suggesting that the expression of ShcC potentially has a function in inhibiting the differentiation of neuroblastoma cells. In addition, marked suppression of in vivo tumorigenicity of TNB1 cells in nude mice was observed by stable knockdown of ShcC protein. These findings indicate that ShcC is a therapeutic target that might induce differentiation in the aggressive type of neuroblastomas.
Miyake
I
I
Growth Factor Division, National Cancer Center Research Institute, Tokyo, Japan.
Ohira
M
M
Nakagawara
A
A
Sakai
R
R
D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007223:Infant; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012307:Risk Factors; D055765:Shc Signaling Adaptor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3
D002352:Carrier Proteins; D034741:RNA, Small Interfering; C122029:SHC3 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D011505:Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases