MicroRNA-720 Regulates E-cadherin-αE-catenin Complex and Promotes Renal Cell Carcinoma

• Published in: Molecular cancer therapeutics Vol. 16; no. 12; pp. 2840 - 2848
• Main Authors: Bhat, Nadeem S, Colden, Melissa, Dar, Altaf A, Saini, Sharanjot, Arora, Prerna, Shahryari, Varahram, Yamamura, Soichiro, Tanaka, Yuichiro, Kato, Taku, Majid, Shahana, Dahiya, Rajvir
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.12.2017
• Subjects: 3' Untranslated regions; AKT protein; Animal models; Animals; Antigens, CD; Apoptosis; Biotechnology; Cadherins - metabolism; Cancer; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; CD44 antigen; Cell Line, Tumor; E-cadherin; Heterografts; Humans; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kinases; Metastases; Metastasis; Mice; Mice, Nude; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Proteins; Renal cell carcinoma; Reporter gene; Ribonucleic acid; RNA; Tissues; Xenografts; β-Catenin
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-17-0400

miRNAs are implicated in regulating cancer progression and metastasis. Here, we show that miR-720 is positively associated with renal cell carcinoma (RCC). Elevated levels of miR-720 were observed in a panel of RCC cell lines and clinical tissues compared with nonmalignant cell line and normal samples. Loss of miR-720 function inhibited proliferation, migration, and invasion and induced apoptosis in RCC cell lines and repressed tumor growth in xenograft mouse models. Conversely, gain of miR-720 function in nonmalignant HK-2 cells induced procancerous characteristics. Silencing of miR-720 caused a marked induction in the levels of endogenous αE-catenin and E-cadherin protein levels in anti720 transfected cells compared with control, whereas miR-720 overexpression in RCC cell lines reduced activity of a luciferase reporter gene fused to the wild-type αE-catenin or E-cadherin 3'UTR compared with nonspecific 3'UTR control, indicating that αE-catenin-E-cadherin complex is a direct and functional target of miR-720 in RCC. We also observed attenuation of β-catenin, CD44, and Akt expression in RCC cells transfected with miR-720 inhibitor compared with control. Furthermore, miR-720 exhibited clinical significance in RCC. Expression of miR-720 significantly distinguished malignant from normal samples. Elevated miR-720 levels positively correlated with higher Fuhrman grade, pathologic stage, and poor overall survival of RCC patients. These findings uncover a new regulatory network in RCC involving metastasis-promoting miR-720 that directly targets expression of key metastasis-suppressing proteins E-cadherin and αE-catenin complex. These results suggest that therapeutic regulation of miR-720 may provide an opportunity to regulate EMT and metastasis in RCC. .