TheHOXgene network in hepatocellular carcinoma

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Abstract

Liver organogenesis and cancerogenesis share common mechanisms.HOXgenes control normal development, primary cellular processes and are characterized by a unique genomic network organization. Less is known about the involvement ofHOXgenes with liver cancerogenesis. The comparison of theHOXgene network expression between nontumorous livers and hepatocellular carcinomas (HCCs) highlights significant differences in the locus AHOXgenes, located on chromosome 7, with a consistent overexpression ofHOXA13mRNA thus validating this gene deregulation as a feature of HCC.HOXA13is a determinant of gut primordia and posterior body structures. Transcriptome analysis of HCC/nontumorous liver mRNAs, selected on the basis ofHOXA13overexpression, recognizes a set of deregulated genes. The matching of these genes with previously reported HCC transcriptome analysis identifies cell-cycle and nuclear pore-related HCC phenotype displaying poor prognosis. HOXA13 and HOXA7 homeoproteins share a consensus sequence that physically links eIF4E nuclear bodies acting on the export of specific mRNAs (c-myc,FGF-2,vascular endothelial growth factor(VEGF),ornithine decarboxylase(ODC) andcyclin D1). We report the protein–protein interaction between HOXA13 and eIF4E in liver cancer cells and the deregulation of eIF4E mRNA and protein in cell cycle/nuclear pore HCC group phenotype and in T4 stage HCCs, respectively. Thus, transcriptional and post-transcriptionalHOXA13deregulation is involved in HCC possibly through the mRNA nuclear export of eIF4E-dependent transcripts.

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