title: Altered HOX and WNT7A expression in human lung cancer.
abstract: 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 beta-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 beta-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.
authors.affiliation: Division of Medical Oncology, and Department of Pathology, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA.
authors.forename: R
authors.initials: R
authors.lastname: Calvo
authors.forename: J
authors.initials: J
authors.lastname: West
authors.forename: W
authors.initials: W
authors.lastname: Franklin
authors.forename: P
authors.initials: P
authors.lastname: Erickson
authors.forename: L
authors.initials: L
authors.lastname: Bemis
authors.forename: E
authors.initials: E
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Helfrich
authors.forename: P
authors.initials: P
authors.lastname: Bunn
authors.forename: J
authors.initials: J
authors.lastname: Roche
authors.forename: E
authors.initials: E
authors.lastname: Brambilla
authors.forename: R
authors.initials: R
authors.lastname: Rosell
authors.forename: R M
authors.initials: RM
authors.lastname: Gemmill
authors.forename: H A
authors.initials: HA
authors.lastname: Drabkin
mesh_terms: D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D009363:Neoplasm Proteins; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D000099261:Homeobox A1 Protein
chemical_list: D004268:DNA-Binding Proteins; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D000099261:Homeobox A1 Protein; C115962:HOXA7 protein, human; C491257:HOXB9 protein, human; C492047:Hoxa7 protein, mouse; C092778:WNT7A protein, human; C490508:Wnt7a protein, mouse; C097899:homeobox protein HOXA9; C092119:Hoxa10 protein, mouse