Expression of lumbosacral HOX genes, crucial in kidney organogenesis, is systematically deregulated in clear cell kidney cancers.

Homeobox-containing genes are involved in different stages of kidney organogenesis, from the early events in intermediate mesoderm to terminal differentiation of glomerular and tubular epithelia. The HOX genes show a unique genomic network organization and regulate normal development. The targeted disruption of paralogous group 11 HOX genes (HOX A11, HOX C11 and HOX D11) results in a complete loss of metanephric kidney induction. Despite a large amount of data are related to the early events in the kidney development, not much is known about HOX genes in advanced kidney organogenesis and carcinogenesis. Here, we compare the expression of the whole HOX gene network in late-stage human foetal kidney development with the same patterns detected in 25 pairs of normal clear cell renal carcinomas (RCCs) and 15 isolated RCC biopsy samples. In the majority of RCCs tested, HOX C11 is upregulated, whereas HOX D11, after an early involvement becomes active again at the 23rd week of the foetal kidney development, is always expressed in normal adult kidneys and is deregulated, together with HOX A11 and lumbosacral locus D HOX genes. Thus, through its function of regulating phenotype cell identity, the HOX network plays an important role in kidney carcinogenesis. Lumbosacral HOX genes are involved in the molecular alterations associated with clear cell kidney cancers and represent, through their deregulation, a molecular mark of tubular epithelial dedifferentiation occurring along tumour evolution, with the restoration of genetic programs associated with kidney organogenesis. The deregulation of lumbosacral HOX genes in RCCs supports (i) the consideration of the HOX gene transcriptome as the potential prognostic tool in kidney carcinogenesis and (ii) the possibility to foresee clinical trials with the purpose of targeting these genes to achieve a therapeutic effect in RCC patients.