Published ahead of print on June 19, 2003, doi:10.1165/rcmb.2003-0061OC Am. J. Respir. Cell Mol. Biol., Volume 29, Number 6, December 2003, 694-701 A more recent version of this article appeared on December 1, 2003
Submitted on February 26, 2003 The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressorHan Kim1,1 Medicine, Columbia University College of Physicans and Surgeons, New York, NY, USA, 2 Medicine, Columbia University College of Physicans and Surgeons, New York, NY, USA; Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China, 3 Pathology, Columbia University College of Physicans and Surgeons, New York, NY, USA, 4 Aventis Pharmaceuticals, Bridgewater, NJ, USA, 5 Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada, 6 Medicine, Boston University, Boston, MA, USA * To whom correspondence should be addressed. E-mail: cap6{at}columbia.edu.
Recently, we used gene expression profiling of lung adenocarcinoma and paired normal tissue from smokers and non-smokers to identify genes and molecular pathways associated with cigarette smoking and lung carcinogenesis. The gene encoding Glypican 3, a glycosylphosphatidylinositol (GPI) 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 cand idate lung tumor suppressor gene whose expression may be regulated by exposure to cigarette smoke and functions to modulate cellular response to exogenous damage.
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