MicroRNA-374b Suppresses Proliferation and Promotes Apoptosis in T-cell Lymphoblastic Lymphoma by Repressing AKT1 and Wnt-16
MicroRNA-374b Suppresses Proliferation and Promotes Apoptosis in T-cell Lymphoblastic Lymphoma by Repressing AKT1 and Wnt-16
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MicroRNA-374b 通过抑制 AKT1 和 Wnt-16 来抑制 T 细胞淋巴母细胞淋巴瘤的增殖并促进细胞凋亡。
DOI：
10.1158/1078-0432.ccr-14-2947
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发表时间：
2015-11-01
影响因子：
11.5
通讯作者：
Cai, Qingqing
中科院分区：
文献类型：
--
作者：
Qian, Dong;Chen, Kailin;Cai, Qingqing
目的：在霍奇金和非霍奇金淋巴瘤（NHL）中，microRNA（miRNA）的失调已被广泛研究;然而，关于miRNA在T细胞淋巴母细胞性淋巴瘤（T-LBL）中的作用知之甚少。本研究旨在探讨miR-374 b在T-LBL发生和治疗中的潜在作用。实验设计：利用MiRCURY LNA阵列构建miR-374 b表达谱。采用实时荧光定量PCR和免疫组化方法检测T-LBL中miR-374 b、AKT 1和Wnt 16的表达。进行双荧光素酶报告基因测定以确认miR-374 b的靶缔合。通过体外和体内研究确定miR-374 b的肿瘤抑制作用。结果：通过micro-RNA微阵列评估了380种miRNAs在5种人类T-LBL组织和5种婴儿胸腺样本中的表达。在原发性T-LBL组织中经常检测到miR-374 b的下调，这与本研究中招募的58名患者的总生存率更差和复发风险增加显著相关。miR-374 b在体外和体内抑制T-LBL细胞增殖，并使细胞对血清饥饿和化疗剂诱导的凋亡敏感。此外，我们还鉴定了两种AKT通路相关分子AKT 1和Wnt 16作为miR-374 b的直接靶点。一致地，在T-LBL患者组织中，AKT 1和Wnt 16表达与miR-374 b水平呈负相关，并且是复发和生存的独立预测因子。结论：我们的数据突出了T-LBL中miR-374 b的分子病因学和临床意义。靶向miR-374 b可能代表了一种新的治疗策略，以改善T-LBL患者的治疗和生存。（C）2015年AACR。
Purpose: Deregulation of microRNA (miRNA) has been extensively investigated in both Hodgkin and non-Hodgkin lymphomas (NHL); however, little is known about the roles of miRNAs in T-cell lymphoblastic lymphoma (T-LBL). The aim of the present study was to investigate the potential roles of miR-374b in the development and treatment of T-LBL.Experimental Design: MiRCURY LNA array was used to generate a miRNA-expressing profile. Real-time quantitative PCR and immunohistochemistry (IHC) were applied to detect the expression of miR-374b, AKT1, and Wnt16 in T-LBL samples. The dual-luciferase reporter assay was conducted to confirm target associations of miR-374b. The tumor-suppressive effect of miR-374b was determined by both in vitro and in vivo studies.Results: The expression of 380 miRNAs was evaluated in five human T-LBL tissues and five infantile thymus samples by micro-RNA microarrays. Downregulation of miR-374b was frequently detected in primary T-LBL tissues, which was significantly associated with worse overall survival and increased risk of recurrence of the 58 patients enrolled in this study. miR-374b suppressed T-LBL cell proliferation in vitro and in vivo and sensitized cells to serum starvation-and chemotherapeutic agent-induced apoptosis. Furthermore, we characterized two AKT pathway-associated molecules, AKT1 and Wnt16, as direct targets of miR-374b. Consistently, in T-LBL patient tissues, AKT1 and Wnt16 expression was inversely correlated with miR-374b levels, and was an independent predictor of recurrence and survival.Conclusions: Our data highlight the molecular etiology and clinical significance of miR-374b in T-LBL. Targeting miR-374b may represent a new therapeutic strategy to improve therapy and survival for T-LBL patients. (C)2015 AACR.