Gene silencing of glypican‐3 in clear cell carcinoma of the ovary renders it more sensitive to the apoptotic agent paclitaxel in vitro and in vivo
Gene silencing of glypican‐3 in clear cell carcinoma of the ovary renders it more sensitive to the apoptotic agent paclitaxel in vitro and in vivo
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DOI：
10.1111/j.1349-7006.2009.01382.x
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发表时间：
2010-01
期刊：
影响因子：
5.7
通讯作者：
T. Umezu;K. Shibata;M. Shimaoka;H. Kajiyama;E. Yamamoto;K. Ino;A. Nawa;T. Senga;F. Kikkawa
中科院分区：
文献类型：
--
作者：
T. Umezu;K. Shibata;M. Shimaoka;H. Kajiyama;E. Yamamoto;K. Ino;A. Nawa;T. Senga;F. Kikkawa
磷脂酰肌醇蛋白聚糖-3（GPC 3）是一种硫酸乙酰肝素蛋白聚糖，通过糖基磷脂酰肌醇（GPI）锚与细胞膜结合，磷脂酰肌醇蛋白聚糖可以调节多种生长和存活因子的活性。我们在此报告GPC 3在卵巢透明细胞癌中表达，而在其他癌中不表达。为了评估表型和潜在的临床前相关性，我们产生了一种卵巢癌细胞系，该细胞系用包含靶向GPC 3的shRNA的质粒稳定转染。我们发现，GPC 3表达沉默的透明细胞癌细胞系（GPC 3 [-]）比GPC 3（+）细胞对紫杉醇更敏感。此外，GPC 3沉默诱导的对紫杉醇的敏感性与细胞凋亡途径的激活相关，如流式细胞术所示。此外，我们使用裸鼠研究了GPC 3对腹膜转移的影响。GPC 3（-）引起的腹膜转移瘤对紫杉醇的敏感性高于GPC 3（+）细胞引起的腹膜转移瘤。这些结果表明，透明细胞癌细胞系中增加的GPC 3表达可能对细胞凋亡起保护作用，因此GPC 3的下调可能是增加透明细胞癌对紫杉醇诱导的细胞凋亡的敏感性的潜在靶点。（Cancer Sci 2009）
Glypican‐3 (GPC3) is a heparan sulfate proteoglycan that is bound to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor, and glypicans can regulate the activity of a wide variety of growth and survival factors. We report here that GPC3 was expressed in clear cell carcinoma of the ovary, and not in other carcinomas. To evaluate the phenotype and potential preclinical relevance, we generated an ovarian cancer cell line stably transfected with plasmids encompassing shRNA targeting GPC3. We show that the clear cell carcinoma cell line with silenced GPC3 expression (GPC3 [−]) was more sensitive to paclitaxel than GPC3 (+) cells. In addition, the GPC3 silencing induced sensitization to paclitaxel was associated with the activation of an apoptosis pathway, as shown by flow cytometry. Moreover, we investigated the effect of GPC3 on peritoneal metastases using nude mice. Peritoneal metastases caused by GPC3 (−) were more sensitive to paclitaxel than those caused by GPC3 (+) cells. These results indicate that increased GPC3 expression in a clear cell carcinoma cell line may play a protective role against apoptosis, and so the downregulation of GPC3 may be a potential target to increase sensitivity to paclitaxel‐induced apoptosis in clear cell carcinoma. (Cancer Sci 2009)