HOX gene expression in normal and neoplastic human kidney

Abstract

As a consequence of transformation, cancer cells generally lose some of their differentiative properties. Thus, alterations interfering with the genetic mechanisms required to maintain embryonic determination could lead to tumorigenesis. Ho‐meobox genes are a network of genes encoding nuclear proteins containing DNA‐binding homeodomains that are highly conserved throughout evolution. They are expressed in a stage‐related fashion in the developing embryo and, in adult life, in normal tissues. In mice and humans, homeobox genes of the HOX family are organized in 4 clusters on different chromosomes which have presumably evolved by duplication of a primordial gene cluster. Strikingly, the order of genes within each cluster is also highly conserved throughout evolution, suggesting that the physical organization of HOX genes might be essential for their expression. Recent reports indicate that homeobox mutant mice display morphological abnormalities or show neoplastic alterations, and that growth factors can turn on homeobox genes. We have studied the expression of the Antennapedia‐like HOX genes in normal human kidney and in renal carcinomas. The great majority of the HOX genes analyzed are expressed in a peculiar manner in normal kidney: blocks of genes, even entire HOX loci, are coordinately regulated. Alterations in HOX gene expression in renal carcinoma can be observed in 2 genes of the HOX‐2 locus, HOX‐2A and HOX‐2E, which are actively expressed in normal kidney and silent in cancer biopsies. The HOX‐3H gene is not expressed in normal kidney whereas the HOX‐3H transcripts are present in renal carcinomas. Homeobox genes within the 4 HOX loci can be aligned on the basis of the maximal sequence homology of their homeodomains: this alignment defines 13 paralogous gene groups. In renal carcinomas, genes of group 10 (HOX‐1D, 2F, 3E, 4B) display a marked difference in their transcript classes when compared to those of normal kidney. Our findings suggest an association between altered HOX gene expression and kidney cancer.