title: Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets.
abstract: 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.
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Yi-Ji
authors.initials: YJ
authors.lastname: Liao
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Mu-Yan
authors.initials: MY
authors.lastname: Cai
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
authors.forename: Tian-Hao
authors.initials: TH
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Shu-Peng
authors.initials: SP
authors.lastname: Chen
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Tumor Interventional Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, China; Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Pei-Hong
authors.initials: PH
authors.lastname: Wu
authors.affiliation: Department of Clinical Oncology, People's Hospital, Wuhan University, Wuhan, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wu
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Yuan
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; State Key Laboratory of Oncology in South China, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.affiliation: The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
mesh_terms: D000328:Adult; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000096:biosynthesis
chemical_list: C534072:MIRN101 microRNA, human; D035683:MicroRNAs; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases