Altered HOX and WNT7A Expression in Human Lung Cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS 2000-11, Vol.97 (23), p.12776-12781
• Main Authors: Calvo, Roser, West, James, Franklin, Wilbur, Erickson, Paul, Bemis, Lynne, Li, Efang, Helfrich, Barbara, Bunn, Paul, Roche, Joelle, Brambilla, Elisabeth, Rosell, Rafael, Gemmill, Robert M., Drabkin, Harry A.
• Format: Article
• Language: English
• Subjects: b-catenin; Biological Sciences; Blotting, Western - methods; Cell Line; Cell Line, Transformed; Cell lines; chromosome 3; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Epithelial cells; Gene Expression Profiling; Genes; Genetic loci; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; HOXA1 gene; HOXA10 gene; HOXA7 gene; HOXA9 gene; HOXB9 gene; Human umbilical vein endothelial cells; Humans; Lung cancer; Lung neoplasms; Lung Neoplasms - genetics; Lungs; Medical research; Neoplasm Proteins; Pathology; Protein Biosynthesis; Proteins - genetics; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors - biosynthesis; Transcription Factors - genetics; Tumor cell line; Tumor Cells, Cultured; Tumors; Wnt Proteins; WNT7A gene
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.97.23.12776

HOX genes encode transcription factors that control patterning and cell fates. 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 HOXB9, we confirmed that elevated RNA was associated with protein overexpression. In some cases, marked HOX overexpression was associated with elevated FGF10 and FGF17. During development, the WNT pathway affects cell fate, polarity, 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 cancers. In immortalized bronchial epithelial cells, WNT7a was lost concomitantly with HOXA1, and a statistically significant correlation between the expression of both genes was observed in lung cancer cell lines. Furthermore, we identified a homozygous deletion of β -catenin in the mesothelioma, NCI-H28, associated with reduced WNT7a and the lowest overall cell line expression of HOXA1, HOXA7, HOXA9, and HOXA10, whereas HOXB9 levels were unaffected. Of note, both WNT7a and β -catenin are encoded on chromosome 3p, which undergoes frequent loss of heterozygosity in these tumors. Our results suggest that alterations in regulatory circuits involving HOX, WNT, and possibly fibroblast growth factor pathways occur frequently in lung cancer.