Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

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-based 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 highly-specific miRNA-based therapies.

MiR-135a functions as a selective killer of malignant glioma

“…This finding is similar to the report about systemic administration of miR-26a. Janaiah Kota et al miR-135a selectively induces apoptosis of glioma S Wu et al (Kota et al, 2009) have characterized that miR-26a is capable of reducing proliferation and inducing tumorspecific apoptosis in hepatoma carcinoma cells. They proposed that as miR-26a is highly expressed in many normal tissues, but specifically downregulated in Mycinduced liver tumor, systemic administration of this therapeutic miRNA is well tolerated.…”

Efficient in vivo microRNA targeting of liver metastasis

“…Therapeutic silencing of miR-122 with locked nucleic acid-modified oligonucleotides led to a long-lasting suppression of HCV viremia and improved liver pathology (Lanford et al, 2010). In addition to targeting of oncogenic miRNAs, administration of miRNAs with tumor suppressor activity, such as miR-26a (Kota et al, 2009), let-7 and miR-34a, has been tested for therapeutic potential in vivo in lung cancer models. For instance, synthetic let-7 oligonucleotides complexed with si-PORT-amine administered by intratumoral injection were able to reduce tumor growth in a lung cancer xenograft model (Trang et al, 2010).…”

Microvesicle-delivery miR-150 promotes tumorigenesis by up-regulating VEGF, and the neutralization of miR-150 attenuate tumor development

“…Previous studies have demonstrated that miRNAs are relevant to cancers (Esquela-Kerscher and Slack, 2006), and anti-miRNA treatments have demonstrated anti-tumor effects on an experimental level (Kota et al, 2009). Previous study has found that miRNAs can be packaged into microvesicles (MVs), which are membranous vesicles that are secreted from most cell types, and transferred to neighboring or distant cells, where these miRNAs can regulate the functions of the recipient cells (Zhang et al, 2010).…”