Department of Hematology and Hematopoietic Stem Cell Transplantation and Cell Immunotherapy Center, Chengdu Military General Hospital of PLA, Chengdu, Sichuan 610083, P.R. China.
Int J Oncol. 2017 Jul;51(1):316-326. doi: 10.3892/ijo.2017.4006. Epub 2017 May 17.
T-cell lymphoblastic lymphoma (T-LBL) is an aggressive malignancy with poor prognosis and high recurrence rate. Long non-coding RNA (lncRNA)-MEG3 is an important tumor suppressor in various cancers. The present study investigated the potential role of maternally expressed gene 3 (MEG3) in the progression of T-LBL. Suppressed expression of MEG3 was detected in T-LBL tissues compared with adjacent histologically normal tissues. Down-regulated level of MEG3 was also found in three T-LBL cell lines (CCRF-CEM, Jurkat and SUP-T1) compared with human T-cell line H9. The proliferation of T-LBL cells was inhibited and cell apoptosis rate was largely promoted when MEG3 was upregulated by a lentiviral vector. Further research revealed that microRNA (miRNA)-214 is a direct target of MEG3. The expression of miR-214 was increased in T-LBL tissues and cell lines compared with control groups. Besides, decreased level of miR-214 was elevated adding miR-214 mimic in SUP-T1 cells transfected with LncRNA-MEG3. Similarly, upregulated level of miR-214 was downregulated adding miR-214 inhibitor in SUP-T1 cells transfected with MEG3 siRNA. Luciferase activity assay further confirmed the targeting relationship between MEG3 and miR-214. Moreover, AIFM2 protein was predicted as a target of miR-214. The expression of AIFM2 was increased by MEG3 and was downregulated by miR-214 mimic. miRNA-214 reversed the effect of MEG3 on inhibiting cell proliferation and inducing cell apoptosis and cell cycle arrest in SUP-T1 cells. Moreover, relative expression of AIFM2 had a positive correlation with the expression of MEG3 and was negatively affected by miR-214. In vivo, MEG3 effectively suppressed tumor growth and the expression of proliferation markers Ki-67 and proliferating cell nuclear antigen (PCNA). Taken together, our research revealed that MEG3 worked as an anti-oncogene in T-LBL, and the MEG3-miR-214-AIFM2 pathway regulated the growth of T-LBL, providing potential prognosis markers as well as new potential targets for T-LBL treatment.
T 细胞淋巴母细胞淋巴瘤（T-LBL）是一种侵袭性恶性肿瘤，预后差，复发率高。长链非编码 RNA（lncRNA）-MEG3 是各种癌症中重要的肿瘤抑制因子。本研究探讨了母系表达基因 3（MEG3）在 T-LBL 进展中的潜在作用。与相邻组织学正常组织相比，T-LBL 组织中检测到 MEG3 表达受抑制。与人类 T 细胞系 H9 相比，在三种 T-LBL 细胞系（CCRF-CEM、Jurkat 和 SUP-T1）中也发现 MEG3 水平下调。通过慢病毒载体上调 MEG3 可抑制 T-LBL 细胞的增殖，并显著促进细胞凋亡。进一步研究表明，microRNA（miRNA）-214 是 MEG3 的直接靶标。与对照组相比，T-LBL 组织和细胞系中 miR-214 的表达增加。此外，在转染 LncRNA-MEG3 的 SUP-T1 细胞中加入 miR-214 模拟物可升高 miR-214 的下调水平。同样，在转染 MEG3 siRNA 的 SUP-T1 细胞中加入 miR-214 抑制剂可降低 miR-214 的上调水平。荧光素酶活性测定进一步证实了 MEG3 和 miR-214 之间的靶向关系。此外，AIFM2 蛋白被预测为 miR-214 的靶标。MEG3 可增加 AIFM2 表达，miR-214 模拟物可降低 AIFM2 表达。miR-214 可逆转 MEG3 对 SUP-T1 细胞增殖抑制和诱导细胞凋亡及细胞周期阻滞的作用。此外，AIFM2 的相对表达与 MEG3 的表达呈正相关，而与 miR-214 呈负相关。体内实验表明，MEG3 可有效抑制肿瘤生长和增殖标志物 Ki-67 和增殖细胞核抗原（PCNA）的表达。综上所述，本研究表明 MEG3 在 T-LBL 中发挥抑癌基因的作用，MEG3-miR-214-AIFM2 通路调节 T-LBL 的生长，为 T-LBL 的治疗提供了潜在的预后标志物和新的潜在靶点。
