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.
Highlights
Neuroblastoma, an embryonal tumor of the sympathetic nervous system, originates from primordial neural crest cells, which are destined for sympathetic differentiation
We show that expression of the majority of class I HOX genes is associated with clinical phenotypes of neuroblastoma
It has been reported that morphological differentiation of neuroblastoma cells upon treatment with retinoic acid (RA) is accompanied by an increase of expression of a number of HOX genes.[20,27,28]
Summary
Neuroblastoma, an embryonal tumor of the sympathetic nervous system, originates from primordial neural crest cells, which are destined for sympathetic differentiation. This pediatric solid tumor shows remarkable variations in clinical presentations ranging from aggressive, therapy-resistant progression to spontaneous regression, which regularly occurs in infants both with localized and metastasized disease. It has been suggested that the physiologic molecular program of neuroblast differentiation and growth control is disrupted in neuroblastoma.[9] This developmental arrest may be reversible in spontaneously regressing neuroblastoma, in which a delayed activation of naturally occurring processes of programmed cell death has been suspected.[10,11,12]. Received 17.10.12; revised 14.2.13; accepted 19.2.13; Edited by G Raschellaexpressed in neuroblastoma cell lines and primary tumors.[19,20] In a recent study, Mao et al.[21] reported that HOXC9 expression is decreased in advanced-stage neuroblastoma and is involved in cell cycle control and the processes of neuroblastoma cell differentiation
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