title: Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma.
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.
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kocak
authors.forename: S
authors.initials: S
authors.lastname: Ackermann
authors.forename: B
authors.initials: B
authors.lastname: Hero
authors.forename: Y
authors.initials: Y
authors.lastname: Kahlert
authors.forename: A
authors.initials: A
authors.lastname: Oberthuer
authors.forename: D
authors.initials: D
authors.lastname: Juraeva
authors.forename: F
authors.initials: F
authors.lastname: Roels
authors.forename: J
authors.initials: J
authors.lastname: Theissen
authors.forename: F
authors.initials: F
authors.lastname: Westermann
authors.forename: H
authors.initials: H
authors.lastname: Deubzer
authors.forename: V
authors.initials: V
authors.lastname: Ehemann
authors.forename: B
authors.initials: B
authors.lastname: Brors
authors.forename: M
authors.initials: M
authors.lastname: Odenthal
authors.forename: F
authors.initials: F
authors.lastname: Berthold
authors.forename: M
authors.initials: M
authors.lastname: Fischer
mesh_terms: D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002675:Child, Preschool; D045304:Cytochromes c / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D000071447:N-Myc Proto-Oncogene Protein; D009365:Neoplasm Regression, Spontaneous / Q000235:genetics*; D009367:Neoplasm Staging; D009423:Nervous System Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D018398:Homeodomain Proteins; C522807:Hoxc9 protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D045304:Cytochromes c; D020169:Caspases