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Identification of lung cancer susceptibility/resistance genes.

Yuan-BS; Baldwin-KT; Jefferson-AM; Lowry-D; Reynolds-SH
Proceedings of the American Association for Cancer Research (AACR) 94th Annual Meeting, July 11-14, 2003, Washington, DC. 2nd edition. Philadelphia, PA: American Association for Cancer Research, 2003 Jul; 44:899
Lung cancer is ranked second only to bladder cancer in the proportion of cases thought to be due to occupational exposures. Genetic factors involved in lung carcinogenesis have been implied by several studies. As an approach to better understand the molecular basis between cancer resistance and cancer susceptibility, we have used analysis of gene expression as a tool to attempt to identify the genes involved in cancer susceptibility/resistance. To identify the genes involved in lung cancer susceptibility/resistance, we carried out a cDNA array analysis, covering 1176 genes, on several mouse lung cancer susceptible (AlJ) cell lines and one mouse lung cancer resistant (C57/ BL) cell line. Thirteen genes were observed by cDNA array analysis to have lower mRNA expression in the lung cancer resistant cell line but higher expression in all of the lung cancer susceptible cell lines. These results were further confirmed by RT-PCR analysis. Among the identified genes, secreted phosphoprotein 1 (SPP-1), heat shock protein p86, tumor rejection antigen gp96 (TRA-gp96), Growth Regulated Oncogene 1 (GR01), insulin-like growth factor binding protein 3, and Nedd-5, all exhibited a dramatic difference (> 5-10 fold) in mRNA expression between lung cancer resistant and lung cancer susceptible cells. In a parallel study, DLC-1, a new candidate tumor suppressor gene for human cancers, showed higher expression in the lung cancer resistant C57/BL cell line but decreased expression in lung cancer susceptible NJ cell lines. Preliminary data obtained by in situ hybridization in non-tumor lung tissues dissected from 6-8 week old mice showed that mRNA expression of SPP-1 and TRA-gp96 was found only in the lung stromal cells of the susceptible A/J mice and not in that of the resistant C57/BL mice. RT-PCR detection of mRNA expression in normal lung tissues of both C57/BL and A/J mice showed the GR01 expressed at a significantly higher level in A/J mice than in C57/BL mice. GR01 gene was reported to be a chemokine. Its enhanced expression is regulated by activation of NF-kappaB, leading to accelerated tumor growth, angiogenesis and metastasis in vivo. In eight pairs of mouse low and high invasive lung adenocarcinoma Cell lines, four showed significantly higher expression of GR01 gene in high invasive cell lines as compared with their low invasive cell lines. The determination of GR01 gene and other genes, identified in this study, in the involvement of lung cancer susceptibility is under further investigation.
Tumors; Tumorigenesis; Cancer; Cell-biology; Cell-damage; Cell-function; Cellular-function; Lung-cancer; Lung-disorders; Genetic-factors; Genetic-disorders; Genetics; Carcinogenesis; Respiratory-system-disorders
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Proceedings of the American Association for Cancer Research (AACR) 94th Annual Meeting, July 11-14, 2003, Washington, DC. 2nd edition