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

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.

Pubmed ID: 19524505

Authors

  • 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

Journal

Cell

Publication Data

June 12, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA120185
  • Agency: NCI NIH HHS, Id: R01 CA120185
  • Agency: NCI NIH HHS, Id: R01 CA120185-01A2
  • Agency: NCI NIH HHS, Id: R01 CA120185-02
  • Agency: NCI NIH HHS, Id: R01 CA120185-03

Mesh Terms

  • Animals
  • Carcinoma, Hepatocellular
  • Cyclin D2
  • Cyclins
  • Dependovirus
  • Disease Models, Animal
  • Genetic Vectors
  • Liver Neoplasms
  • Mice
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc