Theranostics 2017; 7(7):1901-1913. doi:10.7150/thno.19168

Research Paper

Therapeutic Inhibition of miR-4260 Suppresses Colorectal Cancer via Targeting MCC and SMAD4

Junjie Xiao1✉, Dongchao Lv1, Jinzhe Zhou2, Yihua Bei1, Ting Chen1, 3, Muren Hu2, Qiulian Zhou1, Siyi Fu1, Qi Huang2✉

1. Regeneration and Ageing Lab, School of Life Science, Shanghai University, Shanghai 200444, China;
2. Department of General Surgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China;
3. First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, China.

Abstract

Dysregulation of microRNAs (miRNAs, miRs) and their putative target genes have been increasingly reported to contribute to colorectal cancer. However, miRNAs that directly target the mutated in colorectal cancer (MCC) gene, a tumor suppressor which is downregulated or inactivated in colorectal cancer, remain largely unknown. By using an array-based miRNA analysis, we identified a group of miRNAs that were dysregulated in human metastatic versus non-metastatic colorectal cancer tissues. One of these miRNAs, miR-4260, was predicted to target MCC in the miRDB database. Results using human HCT116 and HT29 colorectal cancer cell lines showed that miR-4260 mimic enhanced cell proliferation and migration and reduced apoptosis induced by the chemotherapeutic agent 5-fluorouracil while miR-4260 inhibitor had inverse effects. Furthermore, miR-4260 negatively regulated MCC as well as SMAD4 by directly binding to the 3'untranslational region (3'UTR). Using siRNAs targeting MCC or SMAD4, we showed that upregulation of MCC and SMAD4 was essential to mediate the functional roles of miR-4260 inhibitor in colorectal cancer cells. Our in vivo experiments indicated that inhibition of miR-4260 reduced colorectal tumor growth in nude mice subcutaneously implanted with HCT116 cells. Significantly, miR-4260 was increased in human colorectal cancer tissues with simultaneous downregulation of MCC and SMAD4, strongly suggesting the clinical relevance of targeting miR-4260 in the treatment of colorectal cancer. In summary, we identified miR-4260 as a novel oncomiR for colorectal cancer that targets MCC and SMAD4. Inhibition of miR-4260 can, therefore, be a potential therapeutic strategy for colorectal cancer.

Keywords: Colorectal cancer, miRNA-4260, MCC, SMAD4.

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How to cite this article:
Xiao J, Lv D, Zhou J, Bei Y, Chen T, Hu M, Zhou Q, Fu S, Huang Q. Therapeutic Inhibition of miR-4260 Suppresses Colorectal Cancer via Targeting MCC and SMAD4. Theranostics 2017; 7(7):1901-1913. doi:10.7150/thno.19168. Available from http://www.thno.org/v07p1901.htm