title: The prognostic significance of specific HOX gene expression patterns in ovarian cancer.
abstract: HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. HOX gene expression was determined in ovarian cancer cell lines and primary EOCs by QPCR, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one-way ANOVA and t-tests, using statistical software R and GraphPad. The analysis identified 36 of the 39 HOX genes as being overexpressed in high grade serous EOC compared to normal tissue. We detected a molecular HOX gene-signature that predicted poor outcome. Overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer. In conclusion, this study has shown the HOX genes are highly dysregulated in ovarian cancer with high expression of HOXA13, B6, C13, D1 and D13 being predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum-resistant cancer represents a potentially new therapeutic option that should be further developed and tested in clinical trials.
authors.affiliation: Oncology, School of Biosciences and Medicine, FHMS, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford, GU2 7WG.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Kelly
authors.affiliation: Computational & Systems Biology, School of Biosciences and Medicine, FHMS, University of Surrey, Guildford, GU2 7TE.
authors.forename: Carla
authors.initials: C
authors.lastname: Moller-Levet
authors.affiliation: Oncology, School of Biosciences and Medicine, FHMS, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford, GU2 7WG.
authors.forename: Sophie
authors.initials: S
authors.lastname: McGrath
authors.affiliation: Royal Surrey County Hospital, Egerton Road, Guildford, GU2 7XX.
authors.forename: Simon
authors.initials: S
authors.lastname: Butler-Manuel
authors.affiliation: Royal Surrey County Hospital, Egerton Road, Guildford, GU2 7XX.
authors.forename: Thumuluru
authors.initials: T
authors.lastname: Kavitha Madhuri
authors.affiliation: Computational & Systems Biology, School of Biosciences and Medicine, FHMS, University of Surrey, Guildford, GU2 7TE.
authors.forename: Andrzej M
authors.initials: AM
authors.lastname: Kierzek
authors.affiliation: Oncology, School of Biosciences and Medicine, FHMS, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford, GU2 7WG.
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.affiliation: ICT Building, Institute of Cancer Therapeutics, University of Bradford, West Yorkshire, BD7 1DP.
authors.forename: Richard
authors.initials: R
authors.lastname: Morgan
authors.affiliation: Oncology, School of Biosciences and Medicine, FHMS, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford, GU2 7WG.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Michael
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011379:Prognosis
chemical_list: D009944:Organoplatinum Compounds
keywords: HOX genes; ovarian cancer; prognosis; survival; targeted treatment