Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Oncology

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

  • Text
  • PDF
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

×

Figure 7

TβRIII promotes differentiation to suppress NB proliferation.

Options: View larger image (or click on image) Download as PowerPoint
TβRIII promotes differentiation to suppress NB proliferation.
5Y, SHEP, ...
5Y, SHEP, and SK-N-AS cells selected for stable expression of TβRIII, TβRIII-ΔGAG, empty vector control (EV), shRNA to TβRIII (shTβRIII), or nontargeted shRNA control (shNTC). (A) Proliferation index from 3 replicates (mean ± SEM) of thymidine incorporation, normalized to empty vector or nontargeted shRNA control lines. P < 0.01 (ANOVA); *P < 0.05 (1-sample t test and 2-tailed Student’s t test). (B) Western blot for p21 in stable cell lines, with or without FGF2 treatment (1 ng/ml for 5Y, 10 ng/ml for SHEP). Densitometry for p21 normalized to β-actin is shown as percent control. (C) 5Y stable orthotopic xenografts (13 mice per group). Tumor weights (mean ± SEM) and images (scale bar in cm) after 7 weeks of growth. Different symbol colors represent different cohorts. P < 0.0001 (1-way ANOVA); pairwise comparisons P < 0.0001 EV vs. TβRIII, P < 0.05 EV vs. TβRIII-ΔGAG (Mann-Whitney) Western blots of tumor lysates. Average NF160 densitometry from 3 replicates normalized to β-actin is shown as percent control. **P < 0.01 (1-sample t test). H&E staining of tumors from each group. T, tumor; A, host adrenal cells. Scale bar: 50 μM. (D) SK-N-AS stable orthotopic xenografts. Tumor images after 4 weeks of growth (scale bar in cm). Western blot of tumor lysates for differentiation markers. (E) Tumor weights at 4 weeks (mean ± SEM). Different symbol colors represent different cohorts. *P < 0.05 (Mann-Whitney). (F) Kaplan-Meier survival analysis (10 mice per group). (G) H&E-stained contralateral adrenal glands from mice at 4 weeks (scale bar: 50 μM). Photograph of macroscopic metastasis to the contralateral adrenal gland at the 4-week end point (scale bar in cm).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts