Yamada Nami, Noguchi Shunsuke, Kumazaki Minami, Shinohara Haruka, Miki Kohei, Naoe Tomoki, Akao Yukihiro
Biochim Biophys Acta. 2014 Mar;1843(3):590-602. doi: 10.1016/j.bbamcr.2013.11.022.
Increased expression of miR-128a is often observed in acute lymphoblastic leukaemia (ALL) compared with its expression in acute myeloid leukaemia (AML). The objective of this study was to investigate the role of miR-128a, especially that in the Fas-signalling pathway, in T-cell leukaemia cells. The role of miR-128a in Fas-mediated apoptosis was examined by using Fas-activating antibody (CH-11)-susceptible Jurkat cells and -resistant Jurkat/R cells. Whereas ectopic expression of miR-128a conferred Fas-resistance on Jurkat cells by directly targeting Fas-associated protein with death domain (FADD), antagonizing miR-128a expression sensitized Jurkat/R cells to the Fas-mediated apoptosis through derepression of FADD expression. Myeloid leukaemia HL60 and K562 cells were also CH-11-resistant, sharing a similar resistant mechanism with Jurkat/R cells. Furthermore, CH-11 induced demethylation of the promoter region of miR-128a with resultant up-regulation of miR-128a expression in Jurkat/R cells, which was shown to be a mechanism for the resistance ofJurkat/R cells to Fas-mediated apoptosis. Our results indicate that the induction of miR-128a expression by DNA demethylation is a novel mechanism of resistance to Fas-mediated apoptosis.
与急性髓系白血病（AML）相比，急性淋巴细胞白血病（ALL）中经常观察到miR-128a表达增加。本研究的目的是探讨miR-128a在T细胞白血病细胞中的作用，特别是在Fas信号通路中的作用。通过使用对Fas激活抗体（CH-11）敏感的Jurkat细胞和抗性Jurkat/R细胞，研究了miR-128a在Fas介导的凋亡中的作用。异位表达miR-128a通过直接靶向死亡结构域相关蛋白（FADD）使Jurkat细胞获得Fas抗性，而拮抗miR-128a表达则通过解除FADD表达的抑制使Jurkat/R细胞对Fas介导的凋亡敏感。髓系白血病HL60和K562细胞对CH-11也具有抗性，与Jurkat/R细胞具有相似的抗性机制。此外，CH-11诱导Jurkat/R细胞中miR-128a启动子区域的去甲基化，导致miR-128a表达上调，这被证明是Jurkat/R细胞对Fas介导的凋亡产生抗性的一种机制。我们的结果表明，DNA去甲基化诱导miR-128a表达是对Fas介导的凋亡产生抗性的一种新机制。
