Title : : A novel chemopreventive strategy based on tumor suppressor micrornas produced in bioengineered edible plants
MicroRNAs (miRNAs) are small noncoding RNAs that comprise an emerging class of therapeutic agents with significant potential for the prevention and treatment of many diseases, including cancer. Many different forms of cancer are associated with loss or reduced accumulation of one or more miRNAs that function as tumor suppressors. In animal models, restoration of missing tumor suppressor miRNAs prevents the initiation, progression and/or spread of the disease. However, the current absence of an efficient method for delivery of therapeutic miRNAs is a critical barrier to their use. Here we report our progress toward development of a chemopreventive strategy for miRNA replacement therapy based on ingestion of plant matter that has been bioengineered to produce tumor suppressor miRNAs. We have established edible plant lines (in the model plant Arabidopsis thaliana) that produce high levels of three different mammalian tumor suppressor miRNAs (miR-34a, miR-143 and miR-145). We used ApcMin/+ mice, a well -established animal model of colon cancer, to test the chemopreventive activity of diets containing these putative therapeutic plant tissues. In an ongoing pilot study, we found that ApcMin/+ mice fed the bioengineered plant-based diet in a preventive regimen developed significantly fewer intestinal tumors than mice fed a calorically- and nutritionallymatched control diet without plant tissue. These results raise the intriguing prospect of using edible plants, bioengineered to produce mammalian tumor suppressor miRNAs, as an effective, nontoxic, and inexpensive chemopreventive strategy in humans. Bioengineering of plants to produce miRNAs of any desired sequence is a well-established technology currently used for research purposes in diverse food crops. Thus, using edible plants to produce therapeutic miRNAs is highly feasible and has significant potential in basic, translational, and clinical applications to provide a cost-effective alternative to currently available synthetic RNA production and delivery methods.