Department of Oncology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China; Department of Oncology, North Sichuan Medical College Affiliated Nanchong Central Hospital, Nanchong 637000, China.
Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
Cell Signal. 2020 Sep;73:109697. doi: 10.1016/j.cellsig.2020.109697. Epub 2020 Jun 25.
As the foremost common female malignancy, breast cancer (BC) poses a significant public health stumbling block. Although treatment protocols have improved over the years, the overall prognosis of BC remains unsatisfactory. Extensive investigations have taken place into long non coding RNAs (lncRNAs) pertaining to their involvement in carcinogenesis. The current study in connection with bioinformatics tools aimed to identify the myocardial infarction associated transcript (MIAT) as a BC-related differentially expressed lncRNA in an attempt to elucidate the effect of MIAT in BC cells. MIAT was initially overexpressed while DLG3 was down-regulated in BC. BC cells were subsequently treated with si-MIAT or/and si-DLG3, after which the expressions of DLG3 and the Hippo signaling pathway-related proteins were evaluated to analyze their regulatory mechanism in BC, which indicated that MIAT inhibition up-regulated DLG3 and activated the Hippo signaling pathway to suppress proliferation and promote apoptosis of BC cells. MS-PCR and RIP assays demonstrated that MIAT bound to the methylation proteins DNMT1, DNMT3A and DNMT3B, promoted the methylation of CpG islands in DLG3 promoter and inhibited the DLG3 expression. Moreover, our data suggested that DLG3 could bind to MST2 and regulate LAST1, which prevented the nuclear translocation of YAP. The in vitro results were further verified via the in vivo findings. Taken together, the central findings of our study demonstrate that MIAT silencing inhibits BC progression by means of up-regulating DLG3 via activation of the Hippo signaling pathway, highlighting a novel potential therapeutic target for the treatment of the BC.
作为最常见的女性恶性肿瘤，乳腺癌（BC）是一个重大的公共健康障碍。尽管多年来治疗方案有所改进，但 BC 的总体预后仍然不尽如人意。人们对长链非编码 RNA（lncRNA）进行了广泛的研究，探讨它们在癌症发生中的作用。本研究结合生物信息学工具，旨在确定心肌梗塞相关转录物（MIAT）作为与 BC 相关的差异表达 lncRNA，以阐明 MIAT 在 BC 细胞中的作用。在 BC 中，MIAT 最初过表达，而 DLG3 下调。随后用 si-MIAT 或/和 si-DLG3 处理 BC 细胞，评估 DLG3 和 Hippo 信号通路相关蛋白的表达，以分析其在 BC 中的调控机制，结果表明 MIAT 抑制上调 DLG3 并激活 Hippo 信号通路，抑制 BC 细胞增殖并促进其凋亡。MS-PCR 和 RIP 分析表明，MIAT 与甲基化蛋白 DNMT1、DNMT3A 和 DNMT3B 结合，促进 DLG3 启动子中 CpG 岛的甲基化，抑制 DLG3 的表达。此外，我们的数据表明 DLG3 可以与 MST2 结合并调节 LAST1，从而阻止 YAP 的核转位。体外结果进一步通过体内研究结果得到验证。综上所述，本研究的主要发现表明，通过激活 Hippo 信号通路上调 DLG3，沉默 MIAT 抑制 BC 进展，强调了治疗 BC 的一种新的潜在治疗靶点。
