HOX transcription factors are potential targets and markers in malignant mesothelioma.

Richard Morgan,Sophie Gray,Kevin J Harrington,Cheryl Gillett,Hardev S Pandha,Guy Simpson,Zsuzsanna Tabi,James Spicer

doi:10.1186/s12885-016-2106-7

Abstract

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.

Highlights

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 show that HOX dys-regulation is present in cell lines derived from mesothelioma, and in primary tumors, usually with a significant increase in the expression of those HOX genes that behave as oncogenes
HOX gene expression in mesothelioma-derived cell lines and primary tumors In order to assess the expression of HOX genes in mesothelioma we used QPCR to measure RNA levels in four cell lines derived from this malignancy: NCI-H28, NCIH2052, NCI-H226, and MSTO-211H, together with Met-5A which is derived from non-malignant mesothelium cells (Table 2)

Summary

Introduction

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. The HOX genes are a family of transcription factors characterized by highly conserved DNA- and co-factor binding domains This conservation has been driven by their roles in some of the most fundamental patterning events that underlie early development [1]. Most notable of these is the patterning of the anterior to posterior axis, for which a precise spatial and temporal order in the expression of HOX genes is required. Once PBX has bound it can recruit other specific co-factors, including MEIS, which can further modify HOX activity [6]

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