INSM1 increases N-myc stability and oncogenesis via a positive-feedback loop in neuroblastoma

Insulinoma associated-1 (IA-1/INSM1) gene is exclusively expressed during early embryonic development, but has been found to be re-expressed at high levels in neuroendocrine tumors including neuroblastoma. Using over-expression and knockdown experiments in neuroblastoma cells, we showed that INSM1 i...

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Bibliographic Details
Published in:Oncotarget 2015-11, Vol.6 (34), p.36700-36712
Main Authors: Chen, Chiachen, Breslin, Mary B, Lan, Michael S
Format: Article
Language:English
Subjects:
Animals
Carcinogenesis
Cell Line, Tumor
Cell Proliferation - physiology
Glycogen Synthase Kinase 3 beta - metabolism
Heterografts
Humans
Mice
N-Myc Proto-Oncogene Protein - genetics
N-Myc Proto-Oncogene Protein - metabolism
Neuroblastoma - genetics
Neuroblastoma - metabolism
Neuroblastoma - pathology
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Promoter Regions, Genetic
Proto-Oncogene Proteins c-akt - metabolism
Repressor Proteins - genetics
Repressor Proteins - metabolism
Research Paper
Signal Transduction
Transcription Factors - metabolism
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Summary:Insulinoma associated-1 (IA-1/INSM1) gene is exclusively expressed during early embryonic development, but has been found to be re-expressed at high levels in neuroendocrine tumors including neuroblastoma. Using over-expression and knockdown experiments in neuroblastoma cells, we showed that INSM1 is critical for cell proliferation, BME-coated invasion, and soft agar colony formation. Here, we identified INSM1 as a novel target gene activated by N-myc in N-myc amplified neuroblastoma cells. The Sonic hedgehog signaling pathway induced INSM1 by increasing N-myc expression. INSM1 activated PI3K/AKT/GSK3β pathways to suppress N-myc phosphorylation (Thr-58) and inhibited degradation of N-myc. Inversely, N-myc protein bound to the E2-box region of the INSM1 promoter and activated INSM1 expression. The invasion assay and the xenograft nude mouse tumor model revealed that the INSM1 factor facilitated growth and oncogenesis of neuroblastoma. The current data supports our hypothesis that a positive-feedback loop of sonic hedgehog signaling induced INSM1 through N-myc and INSM1 enhanced N-myc stability contributing to the transformation of human neuroblastoma.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.5485