The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressor
The heparan sulfate proteoglycan GPC3 is a potential lung tumor suppressor
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DOI：
10.1165/rcmb.2003-0061oc
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发表时间：
2003-12-01
影响因子：
6.4
通讯作者：
Powell, CA
中科院分区：
文献类型：
--
作者：
Kim, H;Xu, GL;Powell, CA
最近，我们使用肺腺癌和配对的正常组织的基因表达谱从吸烟者和非吸烟者，以确定基因和分子通路与吸烟和肺癌发生。磷脂酰肌醇蛋白聚糖3（一种糖基磷脂酰肌醇连接的硫酸乙酰肝素蛋白聚糖）的编码基因在肺腺癌中减少。在非恶性肺中，吸烟者与非吸烟者相比，GPC 3表达降低;表明表达与吸烟相关。微阵列结果使用肿瘤和非恶性肺组织的独立队列证实。免疫组织化学研究定位磷脂酰肌醇蛋白聚糖3蛋白表达的肺细支气管上皮细胞，腺癌的起源的潜在细胞的顶端表面。北方印迹分析证实在所有测试的非小细胞肺癌细胞系中均不表达。肺细胞系的药物治疗表明，GPC 3的表达是由启动子超甲基化表观遗传沉默。异位表达GPC 3的人肺癌肿瘤细胞在暴露于依托泊苷时表现出凋亡反应增加，并且当植入裸鼠中时表现出生长抑制。这些发现表明，GPC 3是一个候选的肺肿瘤抑制基因，其表达可能受到香烟烟雾暴露和功能，以调节细胞对外源性损伤的反应。
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.