The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressor.
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.
Kim
Han
H
Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University, 630 West 168th Street, Box 91, New York, New York 10032, USA.
Xu
Guo-Liang
GL
Borczuk
Alain C
AC
Busch
Steve
S
Filmus
Jorge
J
Capurro
Mariana
M
Brody
Jerome S
JS
Lange
Jennifer
J
D'Armiento
Jeanine M
JM
Rothman
Paul B
PB
Powell
Charles A
CA
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000378:metabolism; D045744:Cell Line, Tumor; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D053673:Glypicans; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020545:Respiratory Mucosa / Q000166:cytology / Q000473:pathology / Q000502:physiology; D012907:Smoking / Q000009:adverse effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; C105937:GPC3 protein, human; D053673:Glypicans; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine