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Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model

Janaiah Kota, Raghu R. Chivukula, Kathryn A. O’Donnell, Erik A. Wentzel, Chrystal L. Montgomery, Hun-Way Hwang, Tsung-Cheng Chang, Perumal Vivekanandan, Michael Torbenson, K. Reed Clark, Jerry R. Mendell and Joshua T. Mendell

Cell 137 (6): 1005-1017, June 2009.
doi:10.1016/j.cell.2009.04.021

This week’s exemplary summary and analysis by Anonymous:

A recent report by Kota and colleagues describes the systemic delivery of a tumor suppressive miRNA, miR-26a, to a murine model of hepatocellular carcinoma (HCC). In this study, it was shown that miR-26a, a miRNA previously shown to be down-regulated by the c-Myc oncogene, functions as a tumor suppressor via induction of a G1 arrest in a human HCC cell line. This G1 arrest was ascribed to repression of miR-26 targets Cyclin D2 and Cyclin E2. Furthermore, they described an adeno-associated viral vector that would express miR-26a in combination with eGFP. This virus was then delivered to mice over-expressing c-Myc in the liver, which has previously been shown to induce liver tumors. Compared to tumor-bearing mice infected with a virus expressing only eGFP, tumor-bearing mice infected with the virus expressing both eGFP and miR-26a had a substantial reduction in tumor burden without gross toxicity to the liver and other organs. This provides the first example of systemic miRNA delivery suppressing an established tumor in vivo.

While this observation has important therapeutic implications, there are several limitations to the study. First, while the in vitro data suggests that miR-26a acts as a tumor suppressor via cell cycle arrest, the in vivo data for miR-26a causing cell cycle exit is unconvincing. In particular, the use of Ki67 intensity as a measure of cell cycle status is not legitimate, as Ki67 is either present in cycling cells or absent in non-cycling cells. Thus, it appears that the more likely mechanism of tumor suppression in vivo is apoptosis, due to the robust increase in TUNEL staining. However, it is not clear which targets of miR-26a contribute to increased apoptosis. Moreover, while this study proves that miR-26a can suppress early-stage c-Myc liver tumors, it is not clear whether miR-26a can suppress late-stage, invasive HCC. Since most patients with HCC show up with significantly advanced disease, examination of miR-26a delivery in more aggressive lesions would be an important next step.