Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets

• Published in: PLoS genetics Vol. 11; no. 2; p. e1004873
• Main Authors: Zheng, Fang, Liao, Yi-Ji, Cai, Mu-Yan, Liu, Tian-Hao, Chen, Shu-Peng, Wu, Pei-Hong, Wu, Long, Bian, Xiu-Wu, Guan, Xin-Yuan, Zeng, Yi-Xin, Yuan, Yun-Fei, Kung, Hsiang-Fu, Xie, Dan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2015; Public Library of Science (PLoS)
• Subjects: Adult; Angiogenesis; Animals; Apoptosis; Carcinogenesis - genetics; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell Line, Tumor; Disease; Disease-Free Survival; Epithelial-Mesenchymal Transition - genetics; Experiments; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Hepatocellular carcinoma; Humans; Identification and classification; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Male; Metastasis; Methods; Mice; MicroRNA; MicroRNAs; MicroRNAs - administration & dosage; MicroRNAs - biosynthesis; MicroRNAs - genetics; Middle Aged; Molecular Targeted Therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - therapy; Proteins; rho-Associated Kinases - biosynthesis; RNA sequencing; Rodents; Signal Transduction; Tumorigenesis
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1004873

Targeted therapy based on adjustment of microRNA (miRNA)s activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 replacement therapy to hepatocellular carcinoma (HCC) remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05). In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT) and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets.