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Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma
Erik H. Knelson, … , Karthikeyan Mythreye, Gerard C. Blobe
Erik H. Knelson, … , Karthikeyan Mythreye, Gerard C. Blobe
Published October 15, 2013
Citation Information: J Clin Invest. 2013;123(11):4786-4798. https://doi.org/10.1172/JCI69657.
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Research Article Oncology Article has an altmetric score of 8

Type III TGF-β receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma

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Abstract

Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Comparison of mRNA from benign neuroblastic tumors and neuroblastomas revealed that expression of the type III TGF-β receptor (TGFBR3) decreases with advancing stage of neuroblastoma and this loss correlates with a poorer prognosis. Patients with MYCN oncogene amplification and low TGFBR3 expression were more likely to have an adverse outcome. In vitro, TβRIII expression was epigenetically suppressed by MYCN-mediated recruitment of histone deacetylases to regions of the TGFBR3 promoter. TβRIII bound FGF2 and exogenous FGFR1, which promoted neuronal differentiation of neuroblastoma cells. TβRIII and FGF2 cooperated to induce expression of the transcription factor inhibitor of DNA binding 1 via Erk MAPK. TβRIII-mediated neuronal differentiation suppressed cell proliferation in vitro as well as tumor growth and metastasis in vivo. These studies characterize a coreceptor function for TβRIII in FGF2-mediated neuronal differentiation, while identifying potential therapeutic targets and clinical biomarkers for neuroblastoma.

Authors

Erik H. Knelson, Angela L. Gaviglio, Alok K. Tewari, Michael B. Armstrong, Karthikeyan Mythreye, Gerard C. Blobe

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Figure 1

TβRIII expression is decreased in NB.

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TβRIII expression is decreased in NB.
(A) TGFBR3 expression in the micro...
(A) TGFBR3 expression in the microarray data set. Data are presented as median (horizontal bars) and interquartile range (boxes). P < 0.001, Kruskal-Wallis. *P < 0.05, **P < 0.01, intergroup comparisons (Mann-Whitney). n = 11 benign neuroblastic tumors (ganglioneuroma/ganglioneuroblastoma); n = 79 NB early-stage tumors (INSS stage 1/2); n = 123 NB late-stage tumors (INSS stage 3/4). (B) Immunohistochemistry (IHC) of NB tumor samples using a TβRIII antibody and prebleed control serum. Original magnification, ×20; scale bar: 50 μM. Arrows point to cell-associated staining. (C) Quantification of immunohistochemistry by stage of disease (30 early, 30 late). P < 0.01 for mean immunohistochemistry score (Mann-Whitney). (D) Event-free survival in NB with low (bottom 50%; red) and high (top 50%; blue) TGFBR3 expression in the Oberthuer data set (36). (E) Event-free survival split by stage of disease. (F) I125 TGF-β binding and crosslinking with TβRIII pull-down in NB cell lines compared with S16 Schwann cell line. (D and E) Numbers in parentheses indicate the number of samples. Background and β-actin–normalized integrated density for TβRIII are shown as percent control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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