Centre for Cutaneous Research, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
PLoS One. 2011;6(5):e20271. doi: 10.1371/journal.pone.0020271. Epub 2011 May 25.
The GLI (GLI1/GLI2) transcription factors have been implicated in the development and progression of prostate cancer although our understanding of how they actually contribute to the biology of these common tumours is limited. We observed that GLI reporter activity was higher in normal (PNT-2) and tumourigenic (DU145 and PC-3) androgen-independent cells compared to androgen-dependent LNCaP prostate cancer cells and, accordingly, GLI mRNA levels were also elevated. Ectopic expression of GLI1 or the constitutively active ΔNGLI2 mutant induced a distinct cobblestone-like morphology in LNCaP cells that, regarding the former, correlated with increased GLI2 as well as expression of the basal/stem-like markers CD44, β1-integrin, ΔNp63 and BMI1, and decreased expression of the luminal marker AR (androgen receptor). LNCaP-GLI1 cells were viable in the presence of the AR inhibitor bicalutamide and gene expression profiling revealed that the transcriptome of LNCaP-GLI1 cells was significantly closer to DU145 and PC-3 cells than to control LNCaP-pBP (empty vector) cells, as well as identifying LCN2/NGAL as a highly induced transcript which is associated with hormone independence in breast and prostate cancer. Functionally, LNCaP-GLI1 cells displayed greater clonal growth and were more invasive than control cells but they did not form colonies in soft agar or prostaspheres in suspension suggesting that they do not possess inherent stem cell properties. Moreover, targeted suppression of GLI1 or GLI2 with siRNA did not reverse the transformed phenotype of LNCaP-GLI1 cells nor did double GLI1/GLI2 knockdowns activate AR expression in DU145 or PC-3 cells. As such, early targeting of the GLI oncoproteins may hinder progression to a hormone independent state but a more detailed understanding of the mechanisms that maintain this phenotype is required to determine if their inhibition will enhance the efficacy of anti-hormonal therapy through the induction of a luminal phenotype and increased dependency upon AR function.
GLI（GLI1/GLI2）转录因子已被牵涉到前列腺癌的发生和发展中，尽管我们对它们如何实际影响这些常见肿瘤的生物学特性的理解是有限的。我们观察到，在正常（PNT-2）和致瘤性（DU145 和 PC-3）雄激素非依赖性细胞中，GLI 报告基因活性高于雄激素依赖性 LNCaP 前列腺癌细胞，相应地，GLI mRNA 水平也升高。GLI1 或组成型激活的 ΔNGLI2 突变体的异位表达在 LNCaP 细胞中诱导出独特的鹅卵石样形态，就前者而言，与 GLI2 的增加以及基底/干细胞样标记物 CD44、β1-整合素、ΔNp63 和 BMI1 的表达以及 AR（雄激素受体）的表达降低相关。LNCaP-GLI1 细胞在 AR 抑制剂比卡鲁胺的存在下具有活力，基因表达谱分析表明，LNCaP-GLI1 细胞的转录组与 DU145 和 PC-3 细胞更为相似，而与对照 LNCaP-pBP（空载体）细胞相比，以及确定 LCN2/NGAL 作为一个高度诱导的转录本，其与乳腺癌和前列腺癌中的激素独立性相关。功能上，LNCaP-GLI1 细胞比对照细胞具有更强的克隆生长和侵袭能力，但它们在软琼脂或悬浮液中的前列腺球体中不能形成集落，这表明它们不具有固有干细胞特性。此外，用 siRNA 靶向抑制 GLI1 或 GLI2 并不能逆转 LNCaP-GLI1 细胞的转化表型，也不能激活 DU145 或 PC-3 细胞中 AR 的表达。因此，早期靶向 GLI 癌蛋白可能会阻碍向激素非依赖性状态的进展，但需要更详细地了解维持这种表型的机制，以确定它们的抑制是否会通过诱导管腔表型和增加对 AR 功能的依赖性来增强抗激素治疗的疗效。
