a Comprehensive Cancer Center , Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University , Nanjing , China.
b Department of Oncology, First People's Hospital of Yancheng , Fourth Affiliated Hospital of Nantong University , Yancheng , China.
Cancer Biol Ther. 2019;20(6):886-896. doi: 10.1080/15384047.2019.1579959. Epub 2019 Feb 22.
Long noncoding RNAs are widely acknowledged as a group of regulatory factors in various diseases, especially in cancers. KCNQ1 overlapping transcript 1 (KCNQ1OT1) has been reported as oncogene in human cancers. However, the role of KCNQ1OT1 in colorectal cancer (CRC) has not been fully explained. Based on the database analysis, KCNQ1OT1 was highly expressed in CRC samples and predicted the poor prognosis for CRC patients. Functional experiments revealed that KCNQ1OT1 knockdown negatively affected the proliferation, migration and epithelial-mesenchymal transition (EMT) in CRC cells. Moreover, we identified the cytoplasmic localization of KCNQ1OT1 in CRC cells, indicating the post-transcriptional regulation of KCNQ1OT1 on gene expression. Mechanism experiments including RNA Immunoprecipitation (RIP) assay and dual luciferase reporter assays verified that KCNQ1OT1 acted as a competing endogenous RNA (ceRNA) in CRC by sponging microRNA-217 (miR-217) to up-regulate the expression of zinc finger E-box binding homeobox 1 (ZEB1). Further mechanism investigation revealed that ZEB1 enhanced the transcription activity of KCNQ1OT1 by acting as a transcription activator. Finally, rescue assays were designed to demonstrate the effect of KCNQ1OT1-miR-217-ZEB1 feedback loop on proliferation, migration, and EMT of CRC cells. In brief, our research findings revealed that ZEB1-induced upregulation of KCNQ1OT1 improved the proliferation, migration and EMT formation of CRC cells via regulation of miR-217/ZEB1 axis.
长链非编码 RNA 被广泛认为是多种疾病（尤其是癌症）的一组调节因子。KCNQ1 重叠转录本 1（KCNQ1OT1）已被报道为人类癌症的癌基因。然而，KCNQ1OT1 在结直肠癌（CRC）中的作用尚未得到充分解释。基于数据库分析，KCNQ1OT1 在 CRC 样本中高表达，并预测 CRC 患者的预后不良。功能实验表明，KCNQ1OT1 敲低可负调控 CRC 细胞的增殖、迁移和上皮间质转化（EMT）。此外，我们鉴定了 CRC 细胞中 KCNQ1OT1 的细胞质定位，表明 KCNQ1OT1 对基因表达的转录后调控。包括 RNA 免疫沉淀（RIP）实验和双荧光素酶报告基因实验在内的机制实验证实，KCNQ1OT1 通过海绵 microRNA-217（miR-217）作为竞争性内源 RNA（ceRNA）在 CRC 中发挥作用，从而上调锌指 E 盒结合同源盒 1（ZEB1）的表达。进一步的机制研究表明，ZEB1 通过作为转录激活剂增强 KCNQ1OT1 的转录活性。最后，设计了挽救实验来证明 KCNQ1OT1-miR-217-ZEB1 反馈回路对 CRC 细胞增殖、迁移和 EMT 的影响。总之，我们的研究结果表明，ZEB1 诱导的 KCNQ1OT1 上调通过调节 miR-217/ZEB1 轴改善了 CRC 细胞的增殖、迁移和 EMT 形成。
