Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

Janaiah Kota, Raghu R. Chivukula, Kathryn A O'Donnell-Mendell, Erik A. Wentzel, Chrystal L. Montgomery, Hun Way Hwang, Tsung-Cheng Chang, Perumal Vivekanandan, Michael Torbenson, K. Reed Clark, Jerry R. Mendell, Joshua T Mendell

Research output: Contribution to journalArticle

1289 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1005-1017
Number of pages13
JournalCell
Volume137
Issue number6
DOIs
StatePublished - Jun 12 2009

Fingerprint

Liver Neoplasms
MicroRNAs
Liver
Carcinogenesis
Cells
Therapeutics
Hepatocellular Carcinoma
Cyclin D2
Tissue
Dependovirus
Cell proliferation
Cell Cycle Checkpoints
Viruses
Toxicity
Disease Progression
Tumors
Neoplasms
Cell Proliferation
Modulation
RNA

Keywords

  • HUMDISEASE
  • RNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model. / Kota, Janaiah; Chivukula, Raghu R.; O'Donnell-Mendell, 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.

In: Cell, Vol. 137, No. 6, 12.06.2009, p. 1005-1017.

Research output: Contribution to journalArticle

Kota, J, Chivukula, RR, O'Donnell-Mendell, KA, Wentzel, EA, Montgomery, CL, Hwang, HW, Chang, T-C, Vivekanandan, P, Torbenson, M, Clark, KR, Mendell, JR & Mendell, JT 2009, 'Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model', Cell, vol. 137, no. 6, pp. 1005-1017. https://doi.org/10.1016/j.cell.2009.04.021
Kota, Janaiah ; Chivukula, Raghu R. ; O'Donnell-Mendell, 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. / Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model. In: Cell. 2009 ; Vol. 137, No. 6. pp. 1005-1017.
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