Development of novel miR-129 mimics with enhanced efficacy to eliminate chemoresistant colon cancer stem cells

// Ning Wu 1, 2, * , Andrew Fesler 1, * , Hua Liu 1, * and Jingfang Ju 1 1 Department of Pathology, School of Medicine, Stony Brook University, Stony Brook, NY, USA 2 Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, China * These authors have contributed equally to this work Correspondence to: Jingfang Ju, email: jingfang.ju@stonybrookmedicine.edu Keywords: 5-fluorouracil; miR-129; colorectal cancer; cancer stem cells; chemoresistance Received: September 07, 2017 Accepted: October 13, 2017 Published: November 06, 2017 ABSTRACT Background : Resistance to 5-Fluorouracil (5-FU) based chemotherapy is the major reason for failure of treating patients with advanced colorectal cancer. Materials and methods : In this study, we developed a novel miR-129 mimic with potent efficacy in eliminating resistant colon cancer stem cells both in vitro and in vivo . We integrated 5-FU into miR-129 by replacing Uracil (U) to generate 5-FU-miR-129 mimics (Mimic-1). Results : Mimic-1 is a strong therapeutic candidate with a number of unique features. Mimic-1 can be delivered to cancer cells without any transfection reagents (e.g. lipids, viral vector, nanoparticles). Mimic-1 is more potent at inhibiting cell proliferation and inducing cell cycle arrest at G1 phase than native miR-129 and the other mimics tested, while retaining target specificity. Mimic-1 prevents colon cancer metastasis in vivo without toxicity. Conclusion : This represents a significant advancement in the development of a nontoxic and highly potent miRNA based cancer therapeutics and establishes a foundation for further developing Mimic-1 as a novel anti-cancer therapeutic for treating colorectal cancer.