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Clin Cancer Res. 2003 Nov 15;9(15):5683-92.

Coexpression of insulin receptor-related receptor and insulin-like growth factor 1 receptor correlates with enhanced apoptosis and dedifferentiation in human neuroblastomas.

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University Children's Hospital, Marburg, and. Children's Hospital, Leipzig, Germany.



We compared the expression of the insulin receptor-related receptor (IRR) in primary human neuroblastomas with other biological and clinical parameters and the impact of its expression on prognostic outcome.


We studied 49 neuroblastomas of different clinical stages and histological subtypes for (a) IRR, insulin-like growth factor 1 receptor (IGF-1R), TrkA, p75 neurotrophin receptor, and MYCN mRNA expression by reverse transcription-PCR; (b) MYCN gene amplification by Southern blot analyses; (c) cyclin A protein expression by Western blot analyses indicating proliferation rate; and (d) apoptotic index (AI) by terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick end-labeling assay.


IRR mRNA expression was found in 25 (51%) neuroblastomas and correlated with stages 1, 2, 3, and 4S disease and with age </=12 months at diagnosis. IRR was expressed predominantly in neuroblastomas without MYCN gene amplification and coexpressed with IGF-1R, TrkA, and p75 neurotrophin receptor. IRR mRNA expression also correlated with an undifferentiated histology but not with the proliferation rate. In coexpression with IGF-1R, the IRR was associated with enhanced AI. IRR expression was significantly correlated with a good prognosis in all 49 neuroblastomas (6-year survival probability, 91.8% versus 49.7% for IRR nonexpression; P = 0.003).


IRR expression is a new marker for a favorable prognosis in neuroblastoma that is independent of MYCN amplification and age at diagnosis. Our data suggest an influence of IRR on IGF signaling via IGF-1R because coexpression of these two receptor tyrosine kinases was significantly correlated with an undifferentiated histology, a high AI, and an advanced survival probability.

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