The Heparan Sulfate Proteoglycan GPC3 Is a Potential Lung Tumor Suppressor

Han Kim, Guo Liang Xu, Alain C. Borczuk, Steve Busch, Jorge Filmus, Mariana Capurro, Jerome S. Brody, Jennifer Lange, Jeanine M. D'Armiento, Paul B. Rothman, Charles A. Powell

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)694-701
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume29
Issue number6
DOIs
StatePublished - Dec 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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