Yan Yufeng, Luo Kai, Zhang Huiqin, Chai Weiran
Shanghai Medical College, Fudan University, Shanghai, China.
Hepatogastroenterology. 2013 Jan-Feb;60(121):70-5. doi: 10.5754/hge11801.
BACKGROUND/AIMS: Non-small cell lung cancer (NSCLC) constitutes around 85% of lung cancer cases and is frequently beyond surgical intervention.
Secretory clusterin (sCLU) is found in diverse types of human cancers and is unregulated in a variety of cell lines in response to stress, and enhances cancer cell survival. However, the roles of sCLU in NSCLC are still to be elucidated.
Here we show that RNA interference (RNAi)-mediated sCLU gene silencing with short interference RNA (siRNA) strongly decreased the sCLU mRNA and protein levels, as well as suppressed cell proliferation and induced cell apoptosis. In addition, sCLU siRNA also blocked the PI3K/AKT signaling pathway, and decreased the AKT phosphorylation level, but no change was found in total AKT level. More importantly, PI3K/AKT signaling pathway inhibitor, LY294002, also reduced tumor cell proliferation, which is similar to the result with or without sCLU siRNA treatment.
These results suggest that sCLU plays a positive role in NSCLC cell proliferation, which may be mediated by the PI3K/AKT signaling pathway. Our work in this study demonstrates RNAi-mediated sCLU gene silencing may provide a novel therapeutic strategy in the treatment of NSCLC.
背景/目的：非小细胞肺癌（NSCLC）约占肺癌病例的85%，且常常无法进行手术干预。
分泌型簇集素（sCLU）在多种人类癌症中均有发现，在多种细胞系中，其表达在应激反应下不受调控，并能提高癌细胞的存活率。然而，sCLU在NSCLC中的作用仍有待阐明。
在此我们表明，用小干扰RNA（siRNA）通过RNA干扰（RNAi）介导的sCLU基因沉默可显著降低sCLU的mRNA和蛋白质水平，同时抑制细胞增殖并诱导细胞凋亡。此外，sCLU siRNA还阻断了PI3K/AKT信号通路，并降低了AKT的磷酸化水平，但总AKT水平未发现变化。更重要的是，PI3K/AKT信号通路抑制剂LY294002也降低了肿瘤细胞的增殖，这与有无sCLU siRNA处理的结果相似。
这些结果表明，sCLU在NSCLC细胞增殖中起积极作用，这可能是由PI3K/AKT信号通路介导的。我们在本研究中的工作表明，RNAi介导的sCLU基因沉默可能为NSCLC的治疗提供一种新的治疗策略。
