Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Kaohsiung J Med Sci. 2021 May;37(5):392-401. doi: 10.1002/kjm2.12352. Epub 2021 Feb 21.
A range of circular (Circ) RNAs have been demonstrated to be of therapeutic significance for the treatment of acute lymphoblastic leukemia (ALL). Here, we investigated the mechanisms underlying the action of Circ-PRKDC and the microRNA-653-5p/Reelin (miR-653-5p/RELN) axis in T-cell ALL (T-ALL).Clinical specimens were obtained from patients with T-ALL (n = 39) and healthy controls (n = 30). In each specimen, we determined the expression levels of Circ-PRKDC, miR-653-5p, and RELN. Human T-ALL cells (Jurkat) were transfected with Circ-PRKDC- or miR-653-5p-related sequences to investigate cell proliferation, apoptosis, and autophagy. We also determined the levels of Circ-PRKDC, miR-653-5p, RELN, and signaling proteins related to phosphoinositide 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR). Finally, we decoded the interactions between Circ-PRKDC, miR-653-5p, and RELN. The expression levels of Circ-PRKDC and RELN were upregulated in T-ALL tissues and cells while the levels of miR-653-5p were downregulated. Thereafter, then silencing of Circ-PRKDC, or the enforced expression of miR-653-5p, repressed the expression of RELN and the activation of the PI3K/AKT/mTOR signaling pathway, thus enhancing cell autophagy and apoptosis, and disrupting cell proliferation. Circ-PRKDC acted a sponge for miR-653-5p while miR-653-5p targeted RELN. The knockdown of miR-653-5p abrogated the silencing of Circ-PRKDC-induced effects in T-ALL cells. The depletion of Circ-PRKDC elevated miR-653-5p to silence RELN-mediated PI3K/AKT/mTOR signaling activation, thereby enhancing autophagy and apoptosis in T-ALL cells.
一系列环状 (Circ) RNA 已被证明在治疗急性淋巴细胞白血病 (ALL) 方面具有治疗意义。在这里，我们研究了 Circ-PRKDC 和 microRNA-653-5p/Reelin (miR-653-5p/RELN) 轴在 T 细胞急性淋巴细胞白血病 (T-ALL) 中的作用机制。收集了 39 例 T-ALL 患者和 30 例健康对照者的临床标本，检测 Circ-PRKDC、miR-653-5p 和 RELN 的表达水平。用人 T-ALL 细胞 (Jurkat) 转染 Circ-PRKDC 或 miR-653-5p 相关序列，观察细胞增殖、凋亡和自噬。还测定了 Circ-PRKDC、miR-653-5p、RELN 及与磷酸肌醇 3-激酶 (PI3K)、AKT 和哺乳动物雷帕霉素靶蛋白 (mTOR) 相关的信号蛋白的水平。最后，我们解析了 Circ-PRKDC、miR-653-5p 和 RELN 之间的相互作用。T-ALL 组织和细胞中 Circ-PRKDC 和 RELN 的表达水平上调，而 miR-653-5p 的表达水平下调。此后，沉默 Circ-PRKDC 或强制表达 miR-653-5p 抑制 RELN 的表达和 PI3K/AKT/mTOR 信号通路的激活，从而增强细胞自噬和凋亡，破坏细胞增殖。Circ-PRKDC 作为 miR-653-5p 的海绵，而 miR-653-5p 靶向 RELN。miR-653-5p 的敲低消除了 Circ-PRKDC 沉默诱导的 T-ALL 细胞中的作用。Circ-PRKDC 的耗竭增加了 miR-653-5p 的表达，从而沉默 RELN 介导的 PI3K/AKT/mTOR 信号激活，从而增强 T-ALL 细胞中的自噬和凋亡。
