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| Item Type: | Article |
|---|---|
| Title: | Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma |
| Creators Name: | Kocak, H. and Ackermann, S. and Hero, B. and Kahlert, Y. and Oberthuer, A. and Juraeva, D. and Roels, F. and Theissen, J. and Westermann, F. and Deubzer, H. and Ehemann, V. and Brors, B. and Odenthal, M. and Berthold, F. and Fischer, M. |
| 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. |
| Keywords: | Class I HOX Cluster, Hox-C9, Neuroblastoma, Apoptosis, Differentiation, Spontaneous Regression |
| Source: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Publisher: | Nature Publishing Group |
| Volume: | 4 |
| Page Range: | e586 |
| Date: | 11 April 2013 |
| Official Publication: | https://doi.org/10.1038/cddis.2013.84 |
| PubMed: | View item in PubMed |
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