MiRNA-155 regulates lymphangiogenesis in natural killer/T-cell lymphoma by targeting BRG1
MiRNA-155 regulates lymphangiogenesis in natural killer/T-cell lymphoma by targeting BRG1
复制标题
MiRNA-155 通过靶向 BRG1 调节自然杀伤/T 细胞淋巴瘤中的淋巴管生成。
DOI：
10.1080/15384047.2018.1504721
复制
发表时间：
2019-01-02
影响因子：
3.6
通讯作者：
Zhang, Mingzhi
中科院分区：
文献类型：
--
作者：
Chang, Yu;Cui, Meng;Zhang, Mingzhi
背景：miR-155在自然杀伤/T细胞淋巴瘤（NKTCL）中上调，这是一种侵袭性恶性肿瘤，与疾病进展相关。然而，对miR-155在NKTCL中的生物学活性和潜在机制知之甚少。本研究以miR-155的潜在靶点BRG 1为研究对象，重点探讨miR-155/BRG 1信号通路在NKTCL淋巴管生成调控中的作用。方法：比较miR-155、BRG 1、VEGFC和VEGFD在两种NKTCL细胞系和正常NK细胞中的表达。分别使用miR-155抑制剂和STAT 3抑制剂S31-201评估miR-155和STAT 3的关键作用。两种生物学表型，细胞凋亡和促淋巴管生成，分别在体外通过流式细胞术和淋巴管形成进行了检查，并在体内使用NKTCL异种移植模型。结果：正常NK细胞及两株NKTCL细胞中miR-155表达水平与BRG 1呈负相关，与VEGFC呈正相关。在NKTCL细胞中靶向miR-155显著提高了BRG 1的表达，降低了活化的STAT 3或VEGFC水平，导致细胞凋亡增强和淋巴管生成减少。STAT 3作用于BRG 1的下游，并基本上调节miR-155介导的VEGFC和促淋巴管生成的上调。在体内，靶向miR-155抑制原发性异种移植物生长以及肿瘤相关淋巴管生成。结论：miR-155通过抑制BRG 1的表达，激活STAT 3/VEGFC信号通路，促进淋巴管生成。此外，miR-155还控制NKTCL细胞的活力。因此，靶向miR-155为NKTCL提供了一种新的治疗方法。
Background: miR-155 was up-regulated in natural killer/T-cell lymphoma (NKTCL), an aggressive malignancy, and correlated with disease progression. However, minimal is known on biological activities and underlying mechanisms of miR-155 in NKTCL. In this study, we examined BRG1, a potential target of miR-155, and focused on the miR-155/BRG1 signaling in regulating lymphangiogenesis of NKTCL. Methods: The expression of miR-155, BRG1, VEGFC, and VEGFD was compared between two NKTCL cell lines and normal NK cells. The critical role of miR-155 and STAT3 was assessed using miR-155 inhibitor and STAT3 inhibitor S31-201, respectively. Two biological phenotypes, apoptosis and pro-lymphangiogenesis, were examined in vitro by flow cytometry and lymphatic tube formation, respectively, and in vivo using an NKTCL xenograft model. Results: The miR-155 level negatively correlated with BRG1, but positively with VEGFC in normal NK as well as two NKTCL cell lines. Targeting miR-155 in NKTCL cells significantly boosted BRG1 expression and decreased the activated STAT3 or VEGFC level, leading to enhanced apoptosis and reduced lymphangiogenesis. STAT3 acted downstream of BRG1 and essentially regulated miR-155-mediated up-regulation of VEGFC and pro-lymphangiogenesis. In vivo, targeting miR-155 inhibited primary xenograft growth as well as tumor-associated lymphangiogenesis. Conclusions: By inhibiting BRG1 expression, miR-155 activated STAT3/VEGFC signaling and promoted lymphangiogenesis. In addition, miR-155 also controlled the viability of NKTCL cells. Therefore, targeting miR-155 provides a novel therapy for NKTCL.