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Decreased levels of miR-224 and the passenger strand of miR-221 Increase MBD2, Suppressing Maspin and Promoting Colorectal Tumor Growth and Metastasis in Mice

Kefei Yuan, Ke Xie, John Fox, Huawei Zeng, Hongwei Gao, Canhua Huang, Min Wu
Gastroenterology 2013 v.145 pp. 853-864
colorectal neoplasms, human cell lines, in situ hybridization, lymph nodes, messenger RNA, metastasis, mice, microRNA, quantitative polymerase chain reaction
BACKGROUND & AIMS: Little is known about functions of microRNA (miR) passenger strands (miR*) or their roles in tumor development or progression. We screened for miRs and miR* with levels that were altered in metastatic colorectal cancer (CRC) cells and human tumor samples and investigated their targets and effects on cell function and tumor progression in mice. METHODS: We performed array-based profile analysis to identify miRs with levels that were increased more than 2-fold in metastatic (SW620) CRC cells compared with nonmetastatic (SW480) cells. Quantitative polymerase chain reaction and in situ hybridization analyses were used to measure miRNA levels in CRC cell lines and human tumor samples. We used miRNA duplex mimics or inhibitors to increase and decrease levels of miRNA in CRC cells and assessed their activities and ability to form metastatic xenograft tumors in nude mice. RESULTS: Levels of miR-221* and miR-224 were reduced in metastatic compared with nonmetastatic CRC cells; levels in human tumor samples correlated inversely with tumor stage and metastasis to lymph nodes as well as patient survival times. SW480 cells transfected with miR-221* or miR-224 inhibitors had increased motility in vitro compared with SW480 control cells and formed larger, more metastatic tumors when injected into mice. SW620 cells transfected with miR-221* or miR-224 mimics had reduced migration and motility in vitro and formed smaller tumors with fewer metastases in mice compared with control SW620 cells. We identified the 30 untranslated region of MBD2 messenger RNA as a target of miR-221* and miR-224. MBD2 silences the gene encoding maspin, a suppressor of metastasis. In CRC cells, we found that miR-221* and miR-224 increase the expression of maspin through MBD2 down-regulation.