In Vivo Delivery of miR-34a Sensitizes Lung Tumors to Radiation Through RAD51 Regulation

Maria Angelica Cortez; David Valdecanas; Sharareh Niknam; Heidi J Peltier; Lixia Diao; Uma Giri; Ritsuko Komaki; George A Calin; Daniel R Gomez; Joe Y Chang; John Victor Heymach; Andreas G Bader; James William Welsh

doi:10.1038/mtna.2015.47

Molecular Therapy: Nucleic Acids (Jan 2015)

In Vivo Delivery of miR-34a Sensitizes Lung Tumors to Radiation Through RAD51 Regulation

Maria Angelica Cortez,
David Valdecanas,
Sharareh Niknam,
Heidi J Peltier,
Lixia Diao,
Uma Giri,
Ritsuko Komaki,
George A Calin,
Daniel R Gomez,
Joe Y Chang,
John Victor Heymach,
Andreas G Bader,
James William Welsh

Affiliations

Maria Angelica Cortez: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
David Valdecanas: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Sharareh Niknam: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Heidi J Peltier: Mirna Therapeutics, Inc., Austin, Texas, USA
Lixia Diao: Department of Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Uma Giri: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Ritsuko Komaki: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
George A Calin: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Daniel R Gomez: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Joe Y Chang: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
John Victor Heymach: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Andreas G Bader: Mirna Therapeutics, Inc., Austin, Texas, USA
James William Welsh: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

DOI: https://doi.org/10.1038/mtna.2015.47
Journal volume & issue: Vol. 4, no. C

Abstract

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MiR-34a, an important tumor-suppressing microRNA, is downregulated in several types of cancer; loss of its expression has been linked with unfavorable clinical outcomes in non-small-cell lung cancer (NSCLC), among others. MiR-34a represses several key oncogenic proteins, and a synthetic mimic of miR-34a is currently being tested in a cancer trial. However, little is known about the potential role of miR-34a in regulating DNA damage response and repair. Here, we demonstrate that miR-34a directly binds to the 3’ untranslated region of RAD51 and regulates homologous recombination, inhibiting double-strand-break repair in NSCLC cells. We further demonstrate the therapeutic potential of miR-34a delivery in combination with radiotherapy in mouse models of lung cancer. Collectively, our results suggest that administration of miR-34a in combination with radiotherapy may represent a novel strategy for treating NSCLC.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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