Altered HOX and WNT7A expression in human lung cancer

HOX genes encode transcription factors that control patterning and cell fat es. Alterations in HOX expression have been clearly implicated in leukemia, but their role in most other malignant diseases remains unknown. By using degenerate reverse transcription-PCR and subsequent real-time quantitative assays, we examined HOX expression in lung cancer cell lines, direct tumor- control pairs, and bronchial epithelial cultures. As in leukemia, genes of the HOX9 paralogous group and HOXA10 were frequently overexpressed. For HOX B9, we confirmed that elevated RNA was associated with protein overexpressi on. In some cases, marked HOX overexpression was associated with elevated F CF10 and FGF17. During development the WNT pathway affects cell fate, polar ity, and proliferation, and WNT7a has been implicated in the maintenance of HOX expression. In contrast to normal lung and mortal short-term bronchial epithelial cultures, WNT7a was frequently reduced or absent in lung cancer s. In immortalized bronchial epithelial cells, WNT7a was lost concomitantly with HOXA1, and a statistically significant correlation between the expres sion of both genes was observed in lung cancer cell lines. Furthermore, we identified a homozygous deletion of beta -catenin in the mesothelioma, NCI- H28, associated with reduced WNT7a and the lowest overall cell line express ion of HOXA1, HOXA7, HOXA9 and HOXA10, whereas HOXB9 levels were unaffected . Of note, both WNT7a and beta -catenin are encoded on chromosome 3p, which undergoes frequent loss of heterozygosity in these tumors. Our results sug gest that alterations in regulatory circuits involving HOX, WNT, and possib ly fibroblast growth factor pathways occur frequently in lung cancer.