Pan Chaoyun, Zhu Dihan, Zhuo Jianjiang, Li Limin, Wang Dong, Zhang Chen-Yu, Liu Yuan, Zen Ke
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, China.
Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, 22 Hankou Road, Nanjing, Jiangsu 210093, China.
Sci Rep. 2016 Mar 24;6:23710. doi: 10.1038/srep23710.
Signal regulatory protein α (SIRPα) has been shown to operate as a negative regulator in cancer cell survival. The mechanism underneath such function, however, remains poorly defined. In the present study, we demonstrate that overexpression of SIRPα in acute promyelocytic leukemia (APL) cells results in apoptosis possibly via inhibiting the β-catenin signaling pathway and upregulating Foxo3a. Pharmacological activation of β-catenin signal pathway attenuates apoptosis caused by SIRPα. Interestingly, we also find that the pro-apoptotic effect of SIRPα plays an important role in arsenic trioxide (ATO)-induced apoptosis in APL cells. ATO treatment induces the SIRPα protein expression in APL cells and abrogation of SIRPα induction by lentivirus-mediated SIRPα shRNA significantly reduces the ATO-induced apoptosis. Mechanistic study further shows that induction of SIRPα protein in APL cells by ATO is mediated through suppression of c-Myc, resulting in reduction of three SIRPα-targeting microRNAs: miR-17, miR-20a and miR-106a. In summary, our results demonstrate that SIRPα inhibits tumor cell survival and significantly contributes to ATO-induced APL cell apoptosis.
信号调节蛋白α（SIRPα）已被证明在癌细胞存活中作为负调节因子发挥作用。然而，这种功能背后的机制仍不清楚。在本研究中，我们证明急性早幼粒细胞白血病（APL）细胞中SIRPα的过表达可能通过抑制β-连环蛋白信号通路和上调Foxo3a导致细胞凋亡。β-连环蛋白信号通路的药理学激活减弱了SIRPα引起的细胞凋亡。有趣的是，我们还发现SIRPα的促凋亡作用在三氧化二砷（ATO）诱导的APL细胞凋亡中起重要作用。ATO处理诱导APL细胞中SIRPα蛋白表达，慢病毒介导的SIRPα shRNA消除SIRPα诱导显著降低ATO诱导的细胞凋亡。机制研究进一步表明，ATO诱导APL细胞中SIRPα蛋白是通过抑制c-Myc介导的，导致三种靶向SIRPα的微小RNA：miR-17、miR-20a和miR-106a减少。总之，我们的结果表明SIRPα抑制肿瘤细胞存活，并显著促进ATO诱导的APL细胞凋亡。
