miR-221 silencing blocks hepatocellular carcinoma and promotes survival

Jong Kook Park, Takayuki Kogure, Gerard J. Nuovo, Jinmai Jiang, Lei He, Ji Hye Kim, Mitch A. Phelps, Tracey L. Papenfuss, Carlo M. Croce, Tushar Patel, Thomas D. Schmittgen

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160 Citations (Scopus)

Abstract

Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis because of a lack of any effective therapies. To address this situation, we conducted a preclinical investigation of the therapeutic efficacy of oligonucleotides directed against the oncogenic microRNA miR-221, which has been implicated in HCC. Of 9 chemistries evaluated, we determined that a 2′-O-methyl phosphorothioate-modified anti-miR-221 oligonucleotide was most effective at reducing proliferation in vitro. A cholesterol-modified isoform of anti-miR-221 (cholanti- miR-221) exhibited improved pharmacokinetics and liver tissue distribution compared with unmodified oligonucleotide. Chol-anti-miR-221 significantly reduced miR-221 levels in liver within a week of intravenous administration and in situ hybridization studies confirmed accumulation of the oligonucleotide in tumor cells in vivo. Within the same period, chol-anti-miR-221 reduced tumor cell proliferation and increased markers of apoptosis and cell-cycle arrest, elevating the tumor doubling time and increasing mouse survival. Taken together, our findings offer a preclinical proof of efficacy for chol-anti-miR-221 in a valid orthotopic mouse model of HCC, suggesting that this targeted agent could benefit treatment for patients with advanced HCC.

Original languageEnglish
Pages (from-to)7608-7616
Number of pages9
JournalCancer Research
Volume71
Issue number24
DOIs
Publication statusPublished - 2011 Dec 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Park, J. K., Kogure, T., Nuovo, G. J., Jiang, J., He, L., Kim, J. H., Phelps, M. A., Papenfuss, T. L., Croce, C. M., Patel, T., & Schmittgen, T. D. (2011). miR-221 silencing blocks hepatocellular carcinoma and promotes survival. Cancer Research, 71(24), 7608-7616. https://doi.org/10.1158/0008-5472.CAN-11-1144