This study aims to investigate the role of miR-203–HOTAIR interaction in the suppression of renal cell carcinoma (RCC). We employed series of in vitro assays such as proliferation, invasion, migration, and colony formation along with in vivo tumor xenograft model. Profiling of miR-203 and HOTAIR expression revealed that miR-203 was significantly underexpressed, whereas HOTAIR was overexpressed in RCC cell lines and clinical specimens compared with normal cell line and tissue. Both miR-203 and HOTAIR expression significantly distinguished malignant from normal tissues and significantly correlated with clinicopathologic characteristics of patients. Overexpression of miR-203 significantly inhibited proliferation, migration, and invasion with an induction of apoptosis and cell-cycle arrest. However, HOTAIR suppression resulted in the similar functional effects in the same RCC cell lines. In silico, RNA-22 algorithm showed a binding site for miR-203 in HOTAIR. We observed a direct interaction between miR-203 and HOTAIR by RNA-immunoprecipitation (RIP) and luciferase reporter assays. We show that miR-203–HOTAIR interaction resulted in the inhibition of epithelial-to-mesenchymal transition (EMT) and metastatic genes as indicated by induction of key metastasis-suppressing proteins E-cadherin, claudin (epithelial markers), and PTEN along with induction of tumor suppressor genes p21 and p27. A significant decrease in vimentin (mesenchymal marker), KLF4, and Nanog (stemness markers) was also observed. This is the first report demonstrating miR-203–mediated regulation of HOTAIR induces tumor suppressor effects in RCC by regulating EMT and metastatic pathway genes. Thus, the study suggests that therapeutic regulation of HOTAIR by miR-203 overexpression may provide an opportunity to regulate RCC growth and metastasis. Mol Cancer Ther; 17(5); 1061–9. ©2018 AACR.

中文翻译：

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MicroRNA-203抑制长非编码RNA HOTAIR并通过肾细胞癌的上皮间质转化途径调节肿瘤发生


本研究旨在探讨 miR-203-HOTAIR 相互作用在抑制肾细胞癌 (RCC) 中的作用。我们采用了一系列体外测定，例如增殖、侵袭、迁移和集落形成以及体内肿瘤异种移植模型。 miR-203 和 HOTAIR 表达谱显示，与正常细胞系和组织相比，RCC 细胞系和临床标本中 miR-203 显着表达不足，而 HOTAIR 过表达。 miR-203和HOTAIR表达均能显着区分恶性组织和正常组织，并与患者的临床病理特征显着相关。 miR-203 的过表达显着抑制增殖、迁移和侵袭，并诱导细胞凋亡和细胞周期停滞。然而，HOTAIR 抑制在相同的 RCC 细胞系中产生了类似的功能效应。在计算机模拟中，RNA-22 算法显示了 HOTAIR 中 miR-203 的结合位点。我们通过 RNA 免疫沉淀 (RIP) 和荧光素酶报告基因检测观察到 miR-203 和 HOTAIR 之间的直接相互作用。我们发现，miR-203-HOTAIR 相互作用导致上皮间质转化 (EMT) 和转移基因的抑制，如关键转移抑制蛋白 E-钙粘蛋白、密蛋白（上皮标记物）和 PTEN 以及 PTEN 的诱导所示。诱导肿瘤抑制基因 p21 和 p27。还观察到波形蛋白（间充质标记）、KLF4 和 Nanog（干细胞标记）显着减少。这是第一份证明 miR-203 介导的 HOTAIR 调节通过调节 EMT 和转移途径基因在 RCC 中诱导肿瘤抑制作用的报告。 因此，该研究表明，通过 miR-203 过表达对 HOTAIR 进行治疗调节可能为调节 RCC 生长和转移提供机会。摩尔癌症治疗； 17(5)； 1061–9。 ©2018 AACR。