Therapeutic delivery of miR-26a inhibits cancer cell proliferation and induces tumor-specific apoptosis

By Janaiah Kota, R. Chivukula, Kathryn A. O’Donnell, Erik A. Wentzel, Chrystal L. Montgomery, Hun-Way Hwang, T. Chang, P. Vivekanandan, M. Torbenson, K. R. Clark and 2 more. Cell, 2009

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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.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/eaecbd1cd9655966365e9f756523295afa1cc7b6

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Citations in the corpus

In vivo delivery of miRNAs for cancer therapy: Challenges and strategies (2014, background): “Furthermore, systemic administration of AAV-miR-26 displayed undetectable toxicity [112].”
Tumor angiogenesis: molecular pathways and therapeutic targets (2011, methodology): “Approaches using adeno-associated virus for miRNA delivery have also shown promise in the live”
ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs (2014, background): “It has also been shown that hsa-miR-26a delivery suppresses hepatic tumors in mouse[57], supporting the downregulation of this miRNA in cancer.”
The microcosmos of cancer (2012, background): “For example, in Myc -induced liver tumours, miR-26 delivery by adeno-associated viruses suppresses tumorigenesis by inducing apoptosi”
MYC on the Path to Cancer (2012, background): “The MYC mRNA, which is short lived, is affected by miRNAs (let-7, miR-34, andmiR-145) resulting in translational modulation (Cannell et al., 2010; Christoffersen et al., 2010; Kim et al., 2009; Kress et al., 2011; Sachdeva et al., 2009).”
EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer (2010, background): “Effective delivery of therapeutic microRNAs has been achieved in mice with liver cancer, so this may eventually prove to be feasible in humans (Kota et al., 2009).”
miR-34 – a microRNA replacement therapy is headed to the clinic (2012, background): “A common approach to achieve miRNA expression in vivo is based on vectoral systems that function similarly to those used for traditional gene therapy (Esquela-Kerscher et al., 2008; Kumar et al., 2008; Kota et al., 2009; Qiu et al., 2011).”
Modulation of K-ras-dependent lung tumorigenesis by microRNA-21 (2010, positive): “Recently, gain- and loss-of-function studies in mice demonstrate critical roles for miR-26a and miR-9 in hepatocellular carcinoma and breast cancer metastasis, respectively (Kota et al., 2009; Ma et al., 2010).”
MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review (2012, neutral): “In 2009, Kota et al (Kota et al, 2009) used a systemic administration of miR-26a in a mouse model of HCC using adeno-associated virus (AVV) to inhibit cancer cell proliferation and induction of tumour-speciﬁc apoptosis.”
microRNAs in cancer (2013, background): “Mouse studies that evaluated the therapeutic delivery of tumor-suppressor miRNAs failed to find adverse events associated with the miRNAs and suggested that delivery of miRNA to normal tissues was well tolerated (41, 149).”