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Genetic alterations in mouse lung adenocarcinoma: comparable changes in human lung adenocarcinoma.
Sargent-LM; Lowry-DT; Baldwin-KT; Ruppert-MJ; Ruppert-SM; Kashon-ML; Senft-JR; Vallyathan-V; Johnson-RC; Tyson-FL; Reynolds-RH
Proceedings of the American Association for Cancer Research (AACR) 99th Annual Meeting, April 12-16, 2008, San Diego, California, Abstract 2963. Philadelphia, PA: American Association for Cancer Research, 2008 Apr; 49:701
Lung cancer is the leading cause of cancer death in the Unired States and is ranked second only ro bladder cancer in proportion of cases due to past occupational exposures. The genetic changes associated with progression of the disease are not well understood. We used Spectral Karyotyping (SKY), mapping with fluorescently labeled genomic clones (FISH), comparative genomic hybridization (CGH) on a BAC array, 5 kB NimbleGen CGH array, expression array, real time polymerase chain reaction and Western blot ro analyze 15 primary mouse lung adenocarcinoma and 9 pairs of high and low invasive cell cultures to detect molecular changes The medial portion of chromosome 4 was deleted in 66.0% + 12.0 of all of the cell strains. Duplicalion of the proximal region of chromosome 4 occurred in 68.0% + 11.0 of the cell cultures. The amplification of mouse chromosome 15 was observed in significant number of the high-invasive cell strains (90.0% + 14.0). FISH mapping and CGH array further narrowed the region of deletion of chromosome 4 to 39.6 centimorgans (cM) and the region of duplication to 10 to 35 cM. Chromosome 15 was duplicated. The minimal region of duplication of 15 occurred at band C1. Expression array analysis demonstratcd decreased expression of the apoptotosis associated factors, caspase 8, tumor necrosis factor super family member 8, transforming growth factor beta receptor I, PLK3 and cathepsin D and increased expression of the stem cell associated factor, Kruppel-like factor 4 (KLF4), a tyrosine kinase receptor EphA2. Cyclin E, and a group of ubiquintination factors. Western blotting showed increased protein of Cyclin E and KLF4. Two bands for KLF4 protein bands at 55 KD and 45 KD were identified by Western blot. Blocking experiments demonstrated that the two positive bands were KLF4 specific. Thc amplification of 15 was associated with increased expression of c-myc. Cell strains with the high-invasive phenotype had amplified copy number and expression of KLF4 on chromosome 4 and c-myc on chromosome 15. Funther analysis of human lung adenocarcinoma demonstrated increased KLF4 in 70% of the tumor samples. The homologous linkage groups on human chromosomes 9p21, 1p36 and 9q are altered in human lung adcnocarcinorna. In summary, we have identified alteration in copy number and expression of the genes that may play a functional role in lung cancer development. These results may aid in the identification of mouse and human lung cancer susceptibility genes.
Laboratory-animals; Animals; Animal-studies; Chronic-exposure; Ultraviolet-radiation; Risk-factors; Genes; Genetic-factors; Cancer-rates; Cell-biology; Cell-cultures; Cell-growth; Cell-morphology; Chromosome-disorders; Pulmonary-cancer
Conference/Symposia Proceedings; Abstract
Proceedings of the American Association for Cancer Research (AACR) 99th Annual Meeting, April 12-16, 2008, San Diego, California
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