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Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma.
- Source :
-
Cell death & disease [Cell Death Dis] 2013 Apr 11; Vol. 4, pp. e586. Date of Electronic Publication: 2013 Apr 11. - Publication Year :
- 2013
-
Abstract
- Neuroblastoma is an embryonal malignancy of the sympathetic nervous system. Spontaneous regression and differentiation of neuroblastoma is observed in a subset of patients, and has been suggested to represent delayed activation of physiologic molecular programs of fetal neuroblasts. Homeobox genes constitute an important family of transcription factors, which play a fundamental role in morphogenesis and cell differentiation during embryogenesis. In this study, we demonstrate that expression of the majority of the human HOX class I homeobox genes is significantly associated with clinical covariates in neuroblastoma using microarray expression data of 649 primary tumors. Moreover, a HOX gene expression-based classifier predicted neuroblastoma patient outcome independently of age, stage and MYCN amplification status. Among all HOX genes, HOXC9 expression was most prominently associated with favorable prognostic markers. Most notably, elevated HOXC9 expression was significantly associated with spontaneous regression in infant neuroblastoma. Re-expression of HOXC9 in three neuroblastoma cell lines led to a significant reduction in cell viability, and abrogated tumor growth almost completely in neuroblastoma xenografts. Neuroblastoma growth arrest was related to the induction of programmed cell death, as indicated by an increase in the sub-G1 fraction and translocation of phosphatidylserine to the outer membrane. Programmed cell death was associated with the release of cytochrome c from the mitochondria into the cytosol and activation of the intrinsic cascade of caspases, indicating that HOXC9 re-expression triggers the intrinsic apoptotic pathway. Collectively, our results show a strong prognostic impact of HOX gene expression in neuroblastoma, and may point towards a role of Hox-C9 in neuroblastoma spontaneous regression.
- Subjects :
- Apoptosis genetics
Caspases genetics
Caspases metabolism
Cell Differentiation
Cell Line, Tumor
Child, Preschool
Cytochromes c metabolism
Homeodomain Proteins metabolism
Humans
Infant
Mitochondria metabolism
Mitochondria pathology
N-Myc Proto-Oncogene Protein
Neoplasm Staging
Nervous System Neoplasms metabolism
Nervous System Neoplasms mortality
Nervous System Neoplasms pathology
Neuroblastoma metabolism
Neuroblastoma mortality
Neuroblastoma pathology
Nuclear Proteins genetics
Nuclear Proteins metabolism
Oncogene Proteins genetics
Oncogene Proteins metabolism
Prognosis
Signal Transduction
Survival Analysis
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic
Homeodomain Proteins genetics
Neoplasm Regression, Spontaneous genetics
Nervous System Neoplasms genetics
Neuroblastoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 4
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 23579273
- Full Text :
- https://doi.org/10.1038/cddis.2013.84