Narita Shintaro, So Alan, Ettinger Susan, Hayashi Norihiro, Muramaki Mototsugu, Fazli Ladan, Kim Youngsoo, Gleave Martin E
The Prostate Center, Vancouver General Hospital, British Columbia, Canada.
Clin Cancer Res. 2008 Sep 15;14(18):5769-77. doi: 10.1158/1078-0432.CCR-07-4282.
GLI transcription factors mediate hedgehog signaling and have been implicated in several human malignancies, including prostate cancer. The objectives of this study were to characterize GLI2 expression levels in human prostate cancer cell lines and tissues to test the effect of antisense oligonucleotide (ASO) targeting GLI2 on androgen-independent (AI) prostate cancer cell lines.
A tissue microarray was used to characterize differences in GLI2 expression in benign prostate hyperplasia, prostate cancer treated by neoadjuvant hormonal therapy and AI prostate cancer. The effects of GLI2 ASO on PC-3 cell growth and paclitaxel chemosensitivity were assessed in vitro and in vivo. Oligonucleotide spotted microarray analysis was used to determine alteration in GLI2 coregulated genes after ASO treatment.
The expression of GLI2 was significantly higher in prostate cancer than in benign prostate hyperplasia, decreased after androgen ablation in a time-dependent fashion, but became highly expressed again in AI prostate cancer. GLI2 ASO treatment of PC-3 cells reduced GLI2 mRNA and protein levels in a dose-dependent manner. GLI2 knockdown increased PC-3 cell apoptotic rates and significantly decreased cell growth and modulated levels of apoptosis-related genes, such as Bcl2, Bcl-xL, and clusterin. GLI2 knockdown also changed levels of several cell cycle regulators, such as cyclin D1, p27, and PKC-eta. Systematic administration of GLI2 ASO in athymic mice significantly delayed PC-3 tumor progression and enhanced paclitaxel chemosensitivity.
These findings suggest that increased levels of GLI2 correlates with AI progression and that GLI2 may be a therapeutic target in castrate-resistant prostate cancer.
GLI转录因子介导刺猬信号通路，并且与包括前列腺癌在内的多种人类恶性肿瘤有关。本研究的目的是表征人前列腺癌细胞系和组织中GLI2的表达水平，以测试靶向GLI2的反义寡核苷酸（ASO）对雄激素非依赖性（AI）前列腺癌细胞系的影响。
使用组织微阵列来表征良性前列腺增生、新辅助激素治疗的前列腺癌和AI前列腺癌中GLI2表达的差异。在体外和体内评估GLI2 ASO对PC-3细胞生长和紫杉醇化疗敏感性的影响。使用寡核苷酸点阵微阵列分析来确定ASO处理后GLI2共调控基因的改变。
GLI2在前列腺癌中的表达明显高于良性前列腺增生，在雄激素去除后以时间依赖性方式降低，但在AI前列腺癌中再次高度表达。用GLI2 ASO处理PC-3细胞以剂量依赖性方式降低GLI2 mRNA和蛋白质水平。敲低GLI2增加了PC-3细胞凋亡率，显著降低了细胞生长，并调节了凋亡相关基因的水平，如Bcl2、Bcl-xL和clusterin。敲低GLI2还改变了几种细胞周期调节因子的水平，如细胞周期蛋白D1、p27和蛋白激酶C-η。在无胸腺小鼠中系统性给予GLI2 ASO显著延迟了PC-3肿瘤进展并增强了紫杉醇化疗敏感性。
这些发现表明GLI2水平升高与AI进展相关，并且GLI2可能是去势抵抗性前列腺癌的治疗靶点。
