title: HOX transcription factors are potential targets and markers in malignant mesothelioma.
abstract: BACKGROUND
  The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are dys-regulated in some cancers. In this study we examined the expression and oncogenic function of HOX genes in mesothelioma, a cancer arising from the pleura or peritoneum which is associated with exposure to asbestos.
  
  
  METHODS
  We tested the sensitivity of the mesothelioma-derived lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H226 to HXR9, a peptide antagonist of HOX protein binding to its PBX co-factor. Apoptosis was measured using a FACS-based assay with Annexin, and HOX gene expression profiles were established using RT-QPCR on RNA extracted from cell lines and primary mesotheliomas. The in vivo efficacy of HXR9 was tested in a mouse MSTO-211H flank tumor xenograft model.
  
  
  RESULTS
  We show that HOX genes are significantly dysregulated in malignant mesothelioma. Targeting HOX genes with HXR9 caused apoptotic cell death in all of the mesothelioma-derived cell lines, and prevented the growth of mesothelioma tumors in a mouse xenograft model. Furthermore, the sensitivity of these lines to HXR9 correlated with the relative expression of HOX genes that have either an oncogenic or tumor suppressive function in cancer. The analysis of HOX expression in primary mesothelioma tumors indicated that these cells could also be sensitive to the disruption of HOX activity by HXR9, and that the expression of HOXB4 is strongly associated with overall survival.
  
  
  CONCLUSIONS
  HOX genes are a potential therapeutic target in mesothelioma, and HOXB4 expression correlates with overall survival.
authors: Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Richmond Road, Bradford, BD7 1DP, UK. R.Morgan3@bradford.ac.uk.
authors: Richard
authors: R
authors: Morgan
authors: Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
authors: Guy
authors: G
authors: Simpson
authors: Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
authors: Sophie
authors: S
authors: Gray
authors: Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
authors: Cheryl
authors: C
authors: Gillett
authors: Institute of Cancer and Genetics, University of Cardiff School of Medicine, Cardiff, UK.
authors: Zsuzsanna
authors: Z
authors: Tabi
authors: Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
authors: James
authors: J
authors: Spicer
authors: Targeted Therapy Team, Chester Beatty Laboratories, The Institute of Cancer Research, London, UK.
authors: Kevin J
authors: KJ
authors: Harrington
authors: Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
authors: Hardev S
authors: HS
authors: Pandha
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D010455:Peptides / Q000008:administration & dosage*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C090460:HOXB4 protein, human; C522972:HXR9 peptide; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C083400:PBX1 protein, human