Published ahead of print on June 19, 2003, doi:10.1165/rcmb.2003-0061OC
© 2003 American Thoracic Society DOI: 10.1165/rcmb.2003-0061OC The Heparan Sulfate Proteoglycan GPC3 Is a Potential Lung Tumor SuppressorDepartments of Medicine and Pathology, Columbia College of Physicians and Surgeons, New York, New York; Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China; Aventis Pharmaceuticals, Bridgewater, New Jersey; Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada; and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts Address correspondence to: Charles A. Powell, Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University, 630 West 168th Street, Box 91, New York, New York, 10032. E-mail: cap6{at}columbia.edu Recently, we used gene expression profiling of lung adenocarcinoma and paired normal tissue from smokers and nonsmokers to identify genes and molecular pathways associated with cigarette smoking and lung carcinogenesis. The gene encoding Glypican 3, a glycosylphosphatidylinositol-linked heparan sulfate proteoglycan, was decreased in lung adenocarcinoma. Within nonmalignant lung, GPC3 expression was decreased in smokers compared with nonsmokers; indicating that expression is associated with cigarette smoking. Microarray results were confirmed using an independent cohort of tumors and nonmalignant lung tissues. Immunohistochemical studies localized Glypican 3 protein expression to the apical surface of lung bronchiolar epithelial cells, potential cells of origin for adenocarcinoma. Northern blot analysis demonstrated expression was absent in all tested non–small cell lung carcinoma lines. Pharmacologic treatment of lung cell lines indicated that GPC3 expression was epigenetically silenced by promoter hypermethylation. Human lung carcinoma tumor cells ectopically expressing GPC3 demonstrated increased apoptosis response when exposed to etoposide and growth inhibition when implanted in nude mice. These findings suggest that GPC3 is a candidate lung tumor suppressor gene whose expression may be regulated by exposure to cigarette smoke and functions to modulate cellular response to exogenous damage.
Abbreviations: 5-aza-2'deoxycytidine, 5Aza-dC • green fluorescent protein, GFP • loss of heterozygosity, LOH • phosphate-buffered saline, PBS • Simpson-Golabi-Behmel syndrome, SGBS • Trichostatin, TSA This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
