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Int J Oncol. 2016 Dec;49(6):2255-2264. doi: 10.3892/ijo.2016.3745. Epub 2016 Oct 21.

Regulation of MMP13 by antitumor microRNA-375 markedly inhibits cancer cell migration and invasion in esophageal squamous cell carcinoma.

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Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.


Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies. Recently developed molecular targeted therapies are not available for patients with ESCC. After curative surgical resection, patients frequently suffer distant metastasis and recurrence. Exploration of novel ESCC metastatic pathways may lead to the development of new treatment protocols for this disease. Accordingly, we have sequentially identified microRNA (miRNA)-mediated metastatic pathways in several cancers. Our past studies of miRNA expression signatures have shown that microRNA-375 (miR-375) is frequently reduced in several types of cancers, including ESCC. In the present study, we aimed to investigate novel miR-375-mediated metastatic pathways in ESCC cells. The expression of miR-375 was downregulated in ESCC tissues, and ectopic expression of this miRNA markedly inhibited cancer cell migration and invasion, suggesting that miR-375 acted as an antimetastatic miRNA in ESCC cells. Our strategies for miRNA target searching demonstrated that matrix metalloproteinase 13 (MMP13) was directly regulated by miR-375 in ESCC cells. Overexpression of MMP13 was observed in ESCC clinical tissues, and the expression of MMP13 promoted cancer cell aggressiveness. Moreover, oncogenic genes, including CENPF, KIF14 and TOP2A, were shown to be regulated downstream of MMP13. Taken together, these findings demonstrated that the antitumor miR-375/oncogenic MMP13 axis had a pivotal role in ESCC aggressiveness. These results provide novel insights into the potential mechanisms of ESCC pathogenesis.

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