title: Regulation of MMP13 by antitumor microRNA-375 markedly inhibits cancer cell migration and invasion in esophageal squamous cell carcinoma.
abstract: 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.
authors: Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
authors: Yusaku
authors: Y
authors: Osako
authors: Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.
authors: Naohiko
authors: N
authors: Seki
authors: Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
authors: Yoshiaki
authors: Y
authors: Kita
authors: Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
authors: Keiichi
authors: K
authors: Yonemori
authors: Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.
authors: Keiichi
authors: K
authors: Koshizuka
authors: Department of Functional Genomics, Chiba University Graduate School of Medicine, Chuo-ku, Chiba 260-8670, Japan.
authors: Akira
authors: A
authors: Kurozumi
authors: Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
authors: Itaru
authors: I
authors: Omoto
authors: Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
authors: Ken
authors: K
authors: Sasaki
authors: Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
authors: Yasuto
authors: Y
authors: Uchikado
authors: Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
authors: Hiroshi
authors: H
authors: Kurahara
authors: Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
authors: Kosei
authors: K
authors: Maemura
authors: Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
authors: Shoji
authors: S
authors: Natsugoe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016547:Kinesins / Q000235:genetics; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D008840:Microfilament Proteins; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering; C094772:centromere protein F; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C502598:KIF14 protein, human; D016547:Kinesins; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human