Oncotarget

Research Papers:

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

Chiachen Chen _, Mary B. Breslin and Michael S. Lan

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Oncotarget. 2015; 6:36700-36712. https://doi.org/10.18632/oncotarget.5485

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Abstract

Chiachen Chen1,2, Mary B. Breslin1,2,3, Michael S. Lan1,2,3,4

1The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA

2Laboratory of Diana Helis Henry Medical Research Foundation, New Orleans, LA 70119, USA

3Department of Pediatrics, Louisiana State University Health Sciences Center, LA 70112, USA

4Department of Genetics, Louisiana State University Health Sciences Center, LA 70112, USA

Correspondence to:

Michael S. Lan, e-mail: mlan@chnola-research.org

Keywords: neuroblastoma, N-myc, INSM1, invasion, transformation

Received: June 18, 2015     Accepted: September 18, 2015     Published: October 01, 2015

ABSTRACT

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.


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