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Oligonucleotide Microarray Analysis of Lung Adenocarcinoma in Smokers and Nonsmokers Identifies GPC3 as a Potential Lung Tumor Suppressor* FREE TO VIEW

Charles A. Powell, MD; Guoliang Xu, PhD; Jorge Filmus, PhD; Steven Busch, PhD; Jerome S. Brody, MD; Paul B. Rothman, MD
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*From the Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY.

Correspondence to: Charles A. Powell, MD, Columbia University, 630 W 168th St, Box 91, New York, NY, 10032; e-mail: cap6@columbia.edu

Chest. 2002;121(3_suppl):6S-7S. doi:10.1378/chest.121.3_suppl.6S
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To investigate gene expression profiles associated with cigarette smoking and lung carcinogenesis, we obtained specimens of paired tumor and healthy lung tissue from six nonsmoking individuals who had lung carcinoma and from matched lung cancer patients with a history of smoking. Gene expression analysis was performed using an oligonucleotide array (HuGeneFL Array; Affymetrix; Santa Clara, CA). Hierarchical clustering demonstrated that healthy tissue and tumor tissue clustered separately and that within healthy tissues, those from smokers and nonsmokers clustered separately. Paired t tests were used to create gene lists for probes that demonstrated mean absolute differences (p < 0.01) in samples from tumors compared to healthy tissue for both smokers and nonsmokers. An interrogation of gene lists identified GPC3 as one of several genes the expression of which was lower in the healthy lung tissue of smokers than in nonsmokers and was lower in tumor tissue than in healthy tissue (p < 0.05). GPC3 encodes glypican 3, a glycosylphosphatidyl inositol-linked heparan sulfate proteoglycan. GPC3 alterations are associated with overgrowth in humans (Simpson-Golabi-Behmel syndrome) and in GPC3 null mice. Microarray results have been validated in human lung tissues with RNase protection and with analysis of independent samples (U95Av2 array; Affymetrix). Northern blot analysis demonstrated that GPC3 expression was absent in 9 of 10 lung cancer cell lines. Ectopic expression of rat GPC3 complementary DNA in pMSCV-IRES-GFP infected human lung carcinoma cells (A549 and NCI-H460 cell lines) suggests an association with growth inhibition in vitro. These results are being confirmed by an analysis of tumor formation by these cells in nude mice. In summary, these data suggest that GPC3 is a candidate lung tumor suppressor gene, the expression of which may be regulated by tobacco exposure.




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