miR-221 Silencing Blocks Hepatocellular Carcinoma and Promotes Survival

Abstract

Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis due to 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 (chol-anti-miR-221) exhibited improved pharmacokinetics and liver tissue distribution compared to 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 of advanced HCC patients.

MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches

“…In one notable study, systemic delivery of a cholesterol-tagged antimiR-221 to orthotopic HCC tumors was found to reduce tumor cell proliferation and promote survival. 164 In a second study, anti-miR-221 oligonucleotides were found to exhibit significant antitumor activity in the TG221 transgenic mouse model, where a significant reduction in the number and size of tumors in the treated mice was confirmed with histopathological analyses. Significant downregulation of miR-221 levels has also been detected in liver tissues of anti-miR-221-treated mice, thereby confirming the ability of these molecules to inhibit endogenous miR-221 145 ( Table 2).…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…miR-221 also seems to be a good molecular target. In fact, it has been reported that the 2 -Omethylphosphorothioate-modified oligonucleotide anti-miR-221 reduces cell proliferation and increases the markers of apoptosis and cell cycle arrest, increases the doubling time of the tumor and growth thereby increasing the survival in mice (Park et al, 2011). So also Callegari et al (2012) showed that in transgenic mice in which cirrhosis and cancer are induced by diethylnitrosamine, the overexpression of miR-221 determines an inhibition of its target: CDKI1b/p27 and CDKI1c/p57.…”

miRNAs link metabolic reprogramming to oncogenesis

“…In addition to the LNA technology, cholesterol-modified miRNAs (cholanti-miRs) exhibit improved pharmacokinetics and anti-tumor efficacy. For example, chol-antimiR-221 suppresses effectively liver tumor growth in vivo [140].…”