title: Comprehensive analysis of homeobox genes in Hodgkin lymphoma cell lines identifies dysregulated expression of HOXB9 mediated via ERK5 signaling and BMI1.
abstract: Many members of the nearly 200-strong homeobox gene family have been implicated in cancer, mostly following ectopic expression. In this study we analyzed homeobox gene expression in Hodgkin lymphoma (HL) cell lines. Both reverse transcription-polymerase chain reaction (RT-PCR) using degenerate primers and microarray profiling identified consistently up-regulated HOXB9 expression. Analysis of HOXB9 regulation in HL cells revealed E2F3A and BMI1 as activator and repressor, respectively. Furthermore, a constitutively active ERK5 pathway was identified in all HL cell lines analyzed as well as primary HL cells. Our data show that ERK5 probably mediates HOXB9 expression by repressing BMI1. In addition, expression analysis of the neighboring microRNA gene mir-196a1 revealed coregulation with HOXB9. Functional analysis of HOXB9 by knockdown and overexpression assays indicated their influence on both proliferation and apoptosis in HL cells. In summary, we identified up-regulation of HOXB9 in HL mediated by constitutively active ERK5 signaling which may represent novel therapeutic targets in HL.
authors.affiliation: Human and Animal Cell Cultures, Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), Braunschweig, Germany. sna@dsmz.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Nagel
authors.forename: Christof
authors.initials: C
authors.lastname: Burek
authors.forename: Letizia
authors.initials: L
authors.lastname: Venturini
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.forename: Hilmar
authors.initials: H
authors.lastname: Quentmeier
authors.forename: Corinna
authors.initials: C
authors.lastname: Meyer
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.forename: Roderick A F
authors.initials: RA
authors.lastname: MacLeod
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D006689:Hodgkin Disease / Q000235:genetics* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D005810:Multigene Family; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C069077:BMI1 protein, human; C491257:HOXB9 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D048054:Mitogen-Activated Protein Kinase 7