The Heparan Sulfate Proteoglycan GPC3 Is a Potential Lung Tumor Suppressor

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.

Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors

“…These data suggest that GPC3 may be a lung tumor suppressor gene involved in cigarette smoke-associated lung carcinogenesis. 19 In our study, Xq26 was the most frequently deleted region; however, a relationship between this LOH and cigarette smoke in atypical carcinoids and large cell neuroendocrine carcinomas seems to be unlikely because the same region was unaffected in small cell lung carcinoma, a lung cancer strongly associated with smoke. 20 Interestingly, in a single case of atypical carcinoid (#13), a relation of LOH restricted to the two markers at Xq26 with tumor histological arrangement was found, with the losses occurring only in the solid but not in the trabecular component of the tumor.…”

Differential expression of glypican-3 (GPC3) in lung squamous cell carcinoma and lung adenocarcinoma and its clinical significance

“…Previous studies have demonstrated that GPC3 expression is downregulated in gastric (Ushiku et al, 2009), breast (Xiang et al, 2001), and lung cancers (Kim et al, 2003), but is upregulated in liver cancer and melanoma (Komori et al, 2010). The present study demonstrated that the overall expression rate of GPC3 protein in lung cancer was 45%.…”

Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin–proteasome pathway as a therapeutic target in poor prognosis tumors

“…Cells were seeded at a density of 250 000/well and treated with single drugs and concomitant drug stimulation for 12 h. For sequential drug treatment, each treatment at IC 50 was 12 h. Apoptosis was quantified as reported previously (Kim et al, 2003). Briefly, phosphatidylserine translocation was measured using the Annexin V-PI Apoptosis Detection Kit (BD Biosciences, San Diego, CA, USA) for fluorescence labeling and the FACScan for measurement of the resulting fluorescence.…”