Data from miR-221 Silencing Blocks Hepatocellular Carcinoma and Promotes Survival

<div>Abstract<p>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′-<i>O</i>-methyl phosphorothioate-modified anti-miR-221 oligonucleotide was most effective at reducing proliferation <i>in vitro</i>. A cholesterol-modified isoform of anti-miR-221 (chol-anti-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 <i>in situ</i> hybridization studies confirmed accumulation of the oligonucleotide in tumor cells <i>in vivo</i>. 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. <i>Cancer Res; 71(24); 7608–16. ©2011 AACR</i>.</p></div>