State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Int J Biochem Cell Biol. 2013 Nov;45(11):2530-40. doi: 10.1016/j.biocel.2013.08.007. Epub 2013 Aug 22.
Acetylcholinesterase expression is modulated in various types of tumor, which suggests it is associated with tumor development; however, the mechanism of acetylcholinesterase gene regulation in tumors remains unclear. Here, we report that acetylcholinesterase is aberrantly expressed in non-small cell lung cancer and is an evolutionarily conserved functional target of miR-212. Acetylcholinesterase expression was negatively regulated by miR-212 in vitro and was inversely correlated with miR-212 expression in vivo. In addition, acetylcholinesterase levels were increased, and miR-212 levels decreased, in non-small cell lung cancer cells during cisplatin-induced apoptosis. We further determined that acetylcholinesterase acted as a pro-apoptotic gene in non-small cell lung cells; and attenuated the growth of xenografts in nude mice when upregulated. In contrast, elevated miR-212 levels preserved the protective effect of acetylcholinesterase silencing by RNA interference against cisplatin-induced apoptosis, whereas restoration of miR-212-resistant synaptic acetylcholinesterase expression inhibited the miR-212 anti-apoptotic function. The results demonstrated that miR-212 exerted an anti-apoptotic effect through direct repression of synaptic acetylcholinesterase expression in non-small cell lung cancer cells. Taken together, our study revealed that synaptic acetylcholinesterase may be a tumor suppressor and is modulated by miR-212 in non-small cell lung cancer.
乙酰胆碱酯酶的表达在各种类型的肿瘤中受到调节，这表明它与肿瘤的发展有关；然而，乙酰胆碱酯酶基因在肿瘤中的调节机制尚不清楚。在这里，我们报告乙酰胆碱酯酶在非小细胞肺癌中异常表达，并且是 miR-212 的进化上保守的功能靶标。乙酰胆碱酯酶的表达在体外受到 miR-212 的负调控，并且与体内 miR-212 的表达呈负相关。此外，在顺铂诱导的非小细胞肺癌细胞凋亡过程中，乙酰胆碱酯酶水平升高，miR-212 水平降低。我们进一步确定乙酰胆碱酯酶在非小细胞肺癌细胞中充当促凋亡基因；并且当被上调时，它可以减弱裸鼠异种移植物的生长。相比之下，升高的 miR-212 水平保留了 RNA 干扰沉默乙酰胆碱酯酶对顺铂诱导的凋亡的保护作用，而恢复对 miR-212 具有抗性的突触乙酰胆碱酯酶表达抑制了 miR-212 的抗凋亡功能。结果表明，miR-212 通过直接抑制非小细胞肺癌细胞中的突触乙酰胆碱酯酶表达发挥抗凋亡作用。总之，我们的研究表明，突触乙酰胆碱酯酶可能是一种肿瘤抑制因子，并且在非小细胞肺癌中受到 miR-212 的调节。
