HCP5 is a SMAD3-responsive long non-coding RNA that promotes lung adenocarcinoma metastasis via miR-203/SNAI axis
HCP5 is a SMAD3-responsive long non-coding RNA that promotes lung adenocarcinoma metastasis via miR-203/SNAI axis
复制标题
HCP5是一种SMAD3响应性长非编码RNA，通过miR-203/SNAI轴促进肺腺癌转移
DOI：
10.7150/thno.31097
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Li, Zheng
中科院分区：
文献类型：
--
作者：
Jiang, Lin;Wang, Ranran;Li, Zheng
简介：转化生长因子β（TGF β）信号转导在肺腺癌（LUAD）进展中起着至关重要的作用。然而，参与TGF-β调节的长非编码RNA（lncRNA）在LUAD.Methods的转移仍然知之甚少：我们进行生物信息学分析，以确定推定的lncRNA调节TGF-β/SMAD 3和验证的结果在LUAD细胞中的定量PCR。我们采用荧光素酶报告基因和染色质免疫沉淀技术研究了lncRNA组织相容性白细胞抗原复合物P5（HCP 5）的转录调控，并分别构建了HCP 5基因敲减和HCP 5基因过表达的A549细胞株，以研究HCP 5的功能和作用机制。我们还在小鼠异种移植物和转移模型中证实了我们的发现。结果：发现lncRNA HCP 5受TGF β诱导表达，并受SMAD 3转录调控，促进LUAD肿瘤的生长和转移。此外，HCP 5在LUAD患者的肿瘤组织中过表达，特别是在EGFR和KRAS突变患者和当前吸烟者中。HCP 5高表达与LUAD患者预后不良呈正相关。最后，我们证明了HCP 5的上调通过海绵状的microRNA-203（miR-203）和促进上皮-间质转化（EMT）在LUAD cells.Conclusions增加Snail和Slug的表达：我们的工作表明，lncRNA HCP 5是转录调控SMAD 3和作为一个新的调节TGF β/SMAD信号通路。因此，HCP 5可以作为LUAD的潜在治疗靶点。
Introduction: Transforming growth factor-beta (TGF beta) signaling plays a vital role in lung adenocarcinoma (LUAD) progression. However, the involvement of TGF beta-regulated long non-coding RNAs (lncRNAs) in metastasis of LUAD remains poorly understood.Methods: We performed bioinformatic analyses to identify putative lncRNAs regulated by TGF-beta/SMAD3 and validated the results by quantitative PCR in LUAD cells. We performed luciferase reporter and chromatin immunoprecipitation assays to demonstrate the transcriptional regulation of the lncRNA histocompatibility leukocyte antigen complex P5 (HCP5) we decided to focus on. Stable HCP5 knockdown and HCP5-overexpressing A549 cell variants were generated respectively, to study HCP5 function and understand its mechanism of action. We also confirmed our findings in mouse xenografts and metastasis models. We analyzed the correlation between the level of lncRNA expression with EGFR, KRAS mutations, smoke state and prognostic of LUAD patients.Results: We found that the lncRNA HCP5 is induced by TGF beta and transcriptionally regulated by SMAD3, which promotes LUAD tumor growth and metastasis. Moreover, HCP5 is overexpressed in tumor tissues of patients with LUAD, specifically in patients with EGFR and KRAS mutations and current smoker. HCP5 high expression level is positively correlated with poor prognosis of patients with LUAD. Finally, we demonstrated that upregulation of HCP5 increases the expression of Snail and Slug by sponging the microRNA-203 (miR-203) and promoting epithelial-mesenchymal transition (EMT) in LUAD cells.Conclusions: Our work demonstrates that the lncRNA HCP5 is transcriptionally regulated by SMAD3 and acts as a new regulator in the TGF beta/SMAD signaling pathway. Therefore, HCP5 can serve as a potential therapeutic target in LUAD.