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Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma
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Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma
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Journal Article
Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma
2013
Overview
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.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 692/420
/ Biomedical and Life Sciences
/ Gene Expression Regulation, Neoplastic
/ Homeodomain Proteins - genetics
/ Homeodomain Proteins - metabolism
/ Humans
/ Infant
/ N-Myc Proto-Oncogene Protein
/ Neoplasm Regression, Spontaneous - genetics
/ Nervous System Neoplasms - genetics
/ Nervous System Neoplasms - metabolism
/ Nervous System Neoplasms - mortality
/ Nervous System Neoplasms - pathology
/ Nuclear Proteins - metabolism
/ Oncogene Proteins - genetics
/ Oncogene Proteins - metabolism
/ Original
