Abstract
Abstract Treatment of advanced stage colorectal cancer remains a clinical challenge associated with resistance to fluoropyrimidine based chemotherapy. There is an urgent need to discover and develop new strategies to enhance treatment efficacy in order to improve outcomes for these patients. Non-coding microRNAs (miRNAs) have important functions as oncogenes or tumor suppressor genes in the regulation of cancer development and progression. Recently, miRNAs have emerged as potential therapeutic options. We have previously identified miR-129 as a tumor suppressor miRNA and potential therapeutic candidate in colorectal cancer. The expression of miR-129 is progressively lost in colorectal cancer patients and is an important regulator of apoptosis through the targeting of genes such as BCL-2. miR-129 was also found to enhance 5-flurouracil (5-FU) cytotoxicity in vitro and in vivo. To further developing miR-129 based novel therapeutics in colorectal cancer, we have designed a modified version of miR-129 to enhance stability and efficacy. The miR-129 mimic is significantly more potent in inhibiting proliferation of a panel of colon cancer cell lines than the native miR-129 precursor, with 79% reduction by miR-129 mimic compared to 38% for native precursor. The miR-129 mimic induces profound cell cycle arrest at the G1/S checkpoint. The G1/S ratio increased 3.8 fold compared to control when cells were transfected with miR-129 mimic. We also demonstrated that the miR-129 mimic retains its target specificity to BCL-2, TS and E2F3. The therapeutic potential of miR-129 mimic was demonstrated in vivo mouse colon tumor models as a potent inhibitor of tumor growth and metastasis. As a result, miR-129 mimic has a great potential to be further developed as a novel therapeutic drug for treatment of advanced colorectal cancer. Citation Format: Andrew T. Fesler, Ning Wu, Hua Liu, Jingfang Ju. Development of a novel miR-129 mimic with enhanced therapeutic potential for treatment of resistant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2141. doi:10.1158/1538-7445.AM2017-2141
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