HOX transcription factors are potential targets and markers in malignant mesothelioma

BMC Cancer

Research Article

Cheryl Gillett¹  James Spicer¹  Guy Simpson²  Hardev S. Pandha²  Sophie Gray²  Richard Morgan³  Zsuzsanna Tabi⁴  Kevin J. Harrington⁵ 

[1] Division of Cancer Studies, King’s College London, Guy’s Hospital, London, UK;Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK;Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Richmond Road, BD7 1DP, Bradford, UK;Institute of Cancer and Genetics, University of Cardiff School of Medicine, Cardiff, UK;Targeted Therapy Team, Chester Beatty Laboratories, The Institute of Cancer Research, London, UK;

关键词: Mesothelioma;    HOX;    HXR9;    HOXB4;    Overall survival;   

DOI  :  10.1186/s12885-016-2106-7

 received in 2015-04-20, accepted in 2016-02-01,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionHOX genes are a potential therapeutic target in mesothelioma, and HOXB4 expression correlates with overall survival.

【 授权许可】

CC BY   
© Morgan et al. 2016