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PMID: 19524505 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model.

Cell ·Vol. 137 ·No. 6 ·2009-06-12 ·Pages 1005-17

Kota J, Chivukula RR, O'Donnell KA, Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, Clark KR, Mendell JR, Mendell JT

Abstract

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.

MeSH Terms
Animals Carcinoma, Hepatocellular/genetics,therapy Cyclin D2 Cyclins/metabolism Dependovirus/genetics Disease Models, Animal Genetic Vectors Liver Neoplasms/genetics,therapy Mice MicroRNAs/genetics,metabolism,therapeutic use Proto-Oncogene Proteins c-myc/genetics
Chemicals
CCND2 protein, human CCNE2 protein, human Cyclin D2 Cyclins MIRN26A microRNA, human MYC protein, human MicroRNAs Proto-Oncogene Proteins c-myc
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Kota Janaiah
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Chivukula Raghu R
O'Donnell Kathryn A
Wentzel Erik A
Montgomery Chrystal L
Hwang Hun-Way
Chang Tsung-Cheng
Vivekanandan Perumal
Torbenson Michael
Clark K Reed
Mendell Jerry R
Mendell Joshua T
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2009.04.021
Published
2009-06-12
Pages
1005-17
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2722880
Subset
IM
Grants
NCI NIH HHS · R01 CA120185 · United States
NCI NIH HHS · R01 CA120185-01A2 · United States
NCI NIH HHS · R01 CA120185-02 · United States
NCI NIH HHS · R01 CA120185-03 · United States
Corrections
CommentIn
PMID: 19524500
CommentIn
PMID: 20102759
External Links
PubMed source DOI: 10.1016/j.cell.2009.04.021 PMC Full Text View journal details
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