Department of Pathology, Nanjing Medical University Affiliated Nanjing Hospital (Nanjing First Hospital), Nanjing, 210006, Jiangsu, China.
Dig Dis Sci. 2013 Oct;58(10):2873-80. doi: 10.1007/s10620-013-2735-5. Epub 2013 Aug 4.
Perifosine, an alkylphospholipid, is an Akt inhibitor which inhibits the growth of diverse cancer cells. We have reported its inhibitory effects on the growth of gastric cancer cells recently, but its molecular mechanisms are still largely unknown.
The purpose of this study was to investigate the effect and regulatory mechanism of perifosine in gastric cancer.
Cell viability was determined by sulforhodamine B assay after transiently transfected with AEG-1 specific siRNAs. qRT-PCR and western blot assay were used to determine the mRNA expression and proteins levels of cell signaling molecules examined. Immunohistochemistry was used to detect the AEG-1 expression in 87 gastric carcinomas, 60 dysplasia, and 47 normal gastric mucosa.
Perifosine decreased AEG-1 gene expression along with inhibition of Akt/GSK3β/C-MYC signaling pathway. Knockdown of AEG-1 using siRNA led to significant down-regulation of cyclin D1 expression at both mRNA level and protein level, and inhibited the growth of gastric cancer cells. AEG-1 expression was elevated in gastric dysplasia and cancer tissues compared to normal gastric mucosa (P < 0.01). AEG-1 over-expression correlated with diffuse type of gastric cancer and advanced tumor stages.
Perifosine inhibits the growth of gastric cancer cells possibly through inhibition of the Akt/GSK3β/C-MYC signaling pathway-mediated down-regulation of AEG-1 that subsequently down-regulated cyclin D1. AEG-1 may play an important role in the carcinogenesis and progression of gastric cancer and could be a therapeutic target of perifosine.
前磷酯，一种烷基磷酸脂，是一种 Akt 抑制剂，能抑制多种癌细胞的生长。我们最近报道了它对胃癌细胞生长的抑制作用，但它的分子机制在很大程度上仍然未知。
本研究旨在探讨前磷酯对胃癌的作用及其调控机制。
用 AEG-1 特异性 siRNA 瞬时转染后，通过磺酰罗丹明 B 测定法测定细胞活力。用 qRT-PCR 和 Western blot 检测细胞信号分子的 mRNA 表达和蛋白水平。用免疫组化法检测 87 例胃癌、60 例异型增生和 47 例正常胃黏膜中的 AEG-1 表达。
前磷酯降低 AEG-1 基因表达，同时抑制 Akt/GSK3β/C-MYC 信号通路。用 siRNA 敲低 AEG-1 导致 cyclin D1 的表达在 mRNA 水平和蛋白水平均显著下调，并抑制胃癌细胞的生长。与正常胃黏膜相比，胃癌异型增生和癌组织中 AEG-1 的表达升高（P < 0.01）。AEG-1 过表达与弥漫型胃癌和晚期肿瘤分期相关。
前磷酯可能通过抑制 Akt/GSK3β/C-MYC 信号通路介导的 AEG-1 下调，从而下调 cyclin D1，抑制胃癌细胞的生长。AEG-1 在胃癌的发生和发展中可能起重要作用，可能是前磷酯的治疗靶点。
