EZH2-Mediated microRNA-139-5p Regulates Epithelial-Mesenchymal Transition and Lymph Node Metastasis of Pancreatic Cancer.
EZH2-Mediated microRNA-139-5p Regulates Epithelial-Mesenchymal Transition and Lymph Node Metastasis of Pancreatic Cancer.
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DOI：
10.14348/molcells.2018.0109
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发表时间：
2018-09-30
影响因子：
3.8
通讯作者：
Wang JC
中科院分区：
文献类型：
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作者：
Ma J;Zhang J;Weng YC;Wang JC
胰腺癌（Pancreatic cancer，PC）是最具侵袭性的恶性肿瘤之一，具有高侵袭率、高转移率和不良预后等特点。本研究旨在探讨EZH 2/miR-139- 5 p轴是否影响PC的上皮间质转化（EMT）和淋巴结转移（LNM），以及EZH 2调控miR-139- 5 p的机制。检测EZH 2和miR-139- 5 p在PC及癌旁正常组织中的表达，并分析其与PC临床病理特征的关系。选择人PC细胞系，并用miR-139- 5 p模拟物/抑制剂、EZH 2载体或shEZH 2处理，以验证PC细胞中EZH 2介导的miR-139- 5 p的调节。采用双荧光素酶报告基因分析和染色质免疫沉淀法检测miR-139- 5 p与EZH 2的关系。进行RT-qPCR和Western blot分析以确定miR-139- 5 p、EZH 2和EMT相关标志物以及ZEB 1/2的表达。还分析了肿瘤形成能力和体外细胞活性。在PC组织中检测到高表达的EZH 2和低表达的miR-139- 5 p，并且miR-139- 5 p和EZH 2表达与III/IV期患者、LNM和高分化肿瘤相关。EZH 2通过上调组蛋白3赖氨酸27三甲基化（H3 K27 me 3）抑制miR-139- 5 p的表达。在用miR-139- 5 p模拟物和shEZH 2转染的PC细胞中，EMT、细胞增殖、迁移和侵袭受到阻碍，并且肿瘤形成和LNM减少。EZH 2通过上调H3 K27 me 3抑制miR-139- 5 p的转录，从而下调EZH 2和上调miR-139- 5 p阻止PC中的EMT和LNM。此外，EZH 2/miR-139- 5 p轴呈现为治疗PC的有希望的治疗策略。
Pancreatic cancer (PC) is one of the most aggressive cancers presenting with high rates of invasion and metastasis, and unfavorable prognoses. The current study aims to investigate whether EZH2/miR-139-5p axis affects epithelial-mesenchymal transition (EMT) and lymph node metastasis (LNM) in PC, and the mechanism how EZH2 regulates miR-139-5p. Human PC and adjacent normal tissues were collected to determine expression of EZH2 and miR-139-5p, and their relationship with clinicopathological features of PC. Human PC cell line was selected, and treated with miR-139-5p mimics/inhibitors, EZH2 vector or shEZH2 in order to validate the regulation of EZH2-mediated miR-139-5p in PC cells. Dual-luciferase report gene assay and chromatin immunoprecipitation assay were employed to identify the relationship between miR-139-5p and EZH2. RT-qPCR and Western blot analysis were conducted to determine the expression of miR-139-5p, EZH2 and EMT-related markers and ZEB1/2. Tumor formation ability and in vitro cell activity were also analyzed. Highly-expressed EZH2 and poorly-expressed miR-139-5p were detected in PC tissues, and miR-139-5p and EZH2 expressions were associated with patients at Stage III/IV, with LNM and highly-differentiated tumors. EZH2 suppressed the expression of miR-139-5p through up-regulating Histone 3 Lysine 27 Trimethylation (H3K27me3). EMT, cell proliferation, migration and invasion were impeded, and tumor formation and LNM were reduced in PC cells transfected with miR-139-5p mimics and shEZH2. MiR-139-5p transcription is inhibited by EZH2 through up-regulating H3K27me3, thereby down-regulation of EZH2 and up-regulation of miR-139-5p impede EMT and LNM in PC. In addition, the EZH2/miR-139-5p axis presents as a promising therapeutic strategy for the treatment of PC.