Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1

// Andrew Fesler 1 , Hua Liu 1 and Jingfang Ju 1 1 Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA Correspondence to: Jingfang Ju, email: jingfang.ju@stonybrookmedicine.edu Keywords: 5-fluorouracil; miR-15a; colorectal cancer; chemoresistance; modified miRNA Abbreviations: CSC, colon cancer stem cells; CLL, chronic lymphocytic leukemia; TCGA, The Cancer Genome Atlas; TS, thymidylate synthase Received: October 10, 2017     Accepted: December 08, 2017     Published: December 19, 2017 ABSTRACT Despite advances in colon cancer treatments, resistance and recurrence remain a significant challenge in treating patients. Novel therapeutic strategies are in urgent need to overcome resistance and improve patient outcomes. MicroRNA based therapeutics have potential to help combat resistance. In this study, we have shown that low miR-15a expression correlates with poor patient prognosis. We have demonstrated the therapeutic potential of miR-15a in colon cancer. miR-15a inhibits several important genes ( BCL2, BMI1, YAP1 and DCLK1 ), decreasing cancer progression and resistance. Additionally, by replacing uracil in miR-15a with 5-fluorouracil, we created a novel miR-15a mimic with enhanced therapeutic potential. This mimic maintains target specificity and is more potent than unmodified miR-15a in vitro and inhibits colon tumor metastasis in vivo . This mimic has great potential for therapeutic development for treating colon cancer patients. This novel modification has potential to advance the development of other microRNA based therapeutics beyond miR-15a.