Establish of molecular target therapy for Glypican-3 in ovarian clear cell carcinoma

Glypican-3 （GPC3）是一种硫酸肝素蛋白多糖，通过糖基磷脂酰肌醇（GPI）锚定结合到细胞膜上，glypican可以调节多种生长和生存因子的活性。我们在此报告GPC3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，我们构建了一个卵巢癌细胞系，稳定地转染了包含靶向GPC3的shRNA的质粒。我们发现沉默GPC3表达的透明细胞癌细胞系（GPC3[-]）对紫杉醇的敏感性高于GPC3（+）细胞。此外，流式细胞术显示，GPC3沉默诱导的紫杉醇致敏与凋亡通路的激活有关。此外，我们还利用裸鼠研究了GPC3对腹膜转移瘤的影响。与GPC3（+）细胞相比，GPC3（-）细胞引起的腹膜转移对紫杉醇更敏感。这些结果表明，GPC3在透明细胞癌细胞系中表达升高可能对细胞凋亡具有保护作用，因此下调GPC3可能是增加紫杉醇诱导的透明细胞癌细胞凋亡敏感性的潜在靶点。

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.