系统分析揭示长非编码 RNA（PTAF）介导的促进浆液性卵巢癌中的 EMT 和侵袭转移。
Systematic analyses reveal long non-coding RNA (PTAF)-mediated promotion of EMT and invasion-metastasis in serous ovarian cancer.
机构信息
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, 150081, China.
Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150001, China.
出版信息
Mol Cancer. 2018 Jun 21;17(1):96. doi: 10.1186/s12943-018-0844-7.
BACKGROUND
A deeper mechanistic understanding of epithelial-to-mesenchymal transition (EMT) regulation is needed to improve current anti-metastasis strategies in ovarian cancer (OvCa). This study was designed to investigate the role of lncRNAs in EMT regulation during process of invasion-metastasis in serous OvCa to improve current anti-metastasis strategies for OvCa.
METHODS
We systematically analyzes high-throughput gene expression profiles of both lncRNAs and protein-coding genes in OvCa samples with integrated epithelial (iE) subtype and integrated mesenchymal (iM) subtype labels. Mouse models, cytobiology, molecular biology assays and clinical samples were performed to elucidate the function and underlying mechanisms of lncRNA PTAF-mediated promotion of EMT and invasion-metastasis in serous OvCa.
RESULTS
We constructed a lncRNA-mediated competing endogenous RNA (ceRNA) regulatory network that affects the expression of many EMT-related protein-coding genes in mesenchymal OvCa. Using a combination of in vitro and in vivo studies, we provided evidence that the lncRNA PTAF-miR-25-SNAI2 axis controlled EMT in OvCa. Our results revealed that up-regulated PTAF induced elevated SNAI2 expression by competitively binding to miR-25, which in turn promoted OvCa cell EMT and invasion. Moreover, we found that silencing of PTAF inhibited tumor progression and metastasis in an orthotopic mouse model of OvCa. We then observed a significant correlation between PTAF expression and EMT markers in OvCa patients.
CONCLUSIONS
The lncRNA PTAF, a mediator of TGF-β signaling, can predispose OvCa patients to metastases and may serve as a potential target for anti-metastatic therapies for mesenchymal OvCa patients.
背景
为了改善当前的卵巢癌（OvCa）抗转移策略，需要更深入地了解上皮间质转化（EMT）调控的机制。本研究旨在探讨 lncRNAs 在浆液性 OvCa 侵袭转移过程中 EMT 调控中的作用，以改善当前针对 OvCa 的抗转移策略。
方法
我们系统地分析了具有上皮（iE）亚型和整合间充质（iM）亚型标签的 OvCa 样本中 lncRNAs 和蛋白质编码基因的高通量基因表达谱。进行了小鼠模型、细胞生物学、分子生物学检测和临床样本分析，以阐明 lncRNA PTAF 介导的 EMT 促进和侵袭转移在浆液性 OvCa 中的功能和潜在机制。
结果
我们构建了一个 lncRNA 介导的竞争性内源 RNA（ceRNA）调控网络，该网络影响间充质 OvCa 中许多 EMT 相关蛋白质编码基因的表达。通过体外和体内研究的结合，我们提供了证据表明 lncRNA PTAF-miR-25-SNAI2 轴控制 OvCa 中的 EMT。我们的结果表明，上调的 PTAF 通过与 miR-25 竞争结合来诱导 SNAI2 表达升高，从而促进 OvCa 细胞 EMT 和侵袭。此外，我们发现沉默 PTAF 可抑制 OvCa 的肿瘤进展和转移。然后，我们观察到 PTAF 表达与 OvCa 患者 EMT 标志物之间存在显著相关性。
结论
TGF-β 信号转导的介质 lncRNA PTAF 可使 OvCa 患者易发生转移，可能成为间充质 OvCa 患者抗转移治疗的潜在靶点。
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