title: INSM1 increases N-myc stability and oncogenesis via a positive-feedback loop in neuroblastoma.
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.
authors.affiliation: The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA.|Laboratory of Diana Helis Henry Medical Research Foundation, New Orleans, LA 70119, USA.
authors.forename: Chiachen
authors.initials: C
authors.lastname: Chen
authors.affiliation: The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA.|Laboratory of Diana Helis Henry Medical Research Foundation, New Orleans, LA 70119, USA.|Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Breslin
authors.affiliation: The Research Institute for Children, Children's Hospital, New Orleans, LA 70118, USA.|Laboratory of Diana Helis Henry Medical Research Foundation, New Orleans, LA 70119, USA.|Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.|Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lan
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D012097:Repressor Proteins; D014157:Transcription Factors; C087342:INSM1 protein, human; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: INSM1; N-myc; invasion; neuroblastoma; transformation