Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

被引：2117

作者：

Kota, Janaiah ^{[1
]}

Chivukula, Raghu R. ^{[2
]}

O'Donnell, Kathryn A. ^{[3
,4
]}

Wentzel, Erik A. ^{[2
]}

Montgomery, Chrystal L. ^{[1
]}

Hwang, Hun-Way ^{[2
]}

Chang, Tsung-Cheng ^{[2
]}

Vivekanandan, Perumal ^{[5
]}

Torbenson, Michael ^{[5
]}

Clark, K. Reed ^{[1
,7
]}

Mendell, Jerry R. ^{[1
,7
,8
]}

Mendell, Joshua T. ^{[2
,4
,6
]}

机构：

[1] Nationwide Childrens Hosp, Ctr Gene Therapy, Res Inst, Columbus, OH 43205 USA

[2] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[7] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA

[8] Ohio State Univ, Dept Neurol, Columbus, OH 43210 USA

来源：

CELL | 2009年 / 137卷 / 06期

基金：

美国国家卫生研究院;

关键词：

ADENOASSOCIATED VIRUS VECTORS; IN-VIVO; HEPATOCELLULAR-CARCINOMA; GENE-THERAPY; AAV VECTORS; EXPRESSION; P53; MYC; TRANSDUCTION; APOPTOSIS;

D O I：

10.1016/j.cell.2009.04.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Therapeutic strategies based on modulation of microRNA (miRNA) activity hold great promise due to the ability of these small RNAs to potently influence cellular behavior. In this study, we investigated the efficacy of a miRNA replacement therapy for liver cancer. We demonstrate that hepatocellular carcinoma (HCC) cells exhibit reduced expression of miR-26a, a miRNA that is normally expressed at high levels in diverse tissues. Expression of this miRNA in liver cancer cells in vitro induces cell-cycle arrest associated with direct targeting of cyclins D2 and E2. Systemic administration of this miRNA in a mouse model of HCC using adeno-associated virus (AAV) results in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression without toxicity. These findings suggest that delivery of miRNAs that are highly expressed and therefore tolerated in normal tissues but lost in disease cells may provide a general strategy for miRNA replacement therapies.

引用

页码：1005 / 1017

页数：13

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