miR-655 Is an EMT-Suppressive MicroRNA Targeting ZEB1 and TGFBR2

被引:100
作者
Harazono, Yosuke [1 ,6 ]
Muramatsu, Tomoki [1 ,5 ]
Endo, Hironori [1 ,6 ]
Uzawa, Narikazu [6 ]
Kawano, Tatsuyuki [7 ]
Harada, Kiyoshi [6 ]
Inazawa, Johji [1 ,4 ,5 ]
Kozaki, Ken-ichi [1 ,2 ,3 ,4 ]
机构
[1] Tokyo Med & Dent Univ, Dept Mol Cytogenet, Tokyo, Japan
[2] Tokyo Med & Dent Univ, Med Res Inst, Dept Therapeut Genom, Tokyo, Japan
[3] Tokyo Med & Dent Univ, Sch Biomed Sci, Tokyo, Japan
[4] Tokyo Med & Dent Univ, Hard Tissue Genome Res Ctr, Dept Genome Med, Tokyo, Japan
[5] Tokyo Med & Dent Univ, Global Ctr Excellence GCOE Program Int Res Ctr Mo, Tokyo, Japan
[6] Tokyo Med & Dent Univ, Dept Maxillofacial Surg, Tokyo, Japan
[7] Tokyo Med & Dent Univ, Dept Esophagogastr Surg, Tokyo, Japan
来源
PLOS ONE | 2013年 / 8卷 / 05期
关键词
EPITHELIAL-MESENCHYMAL TRANSITION; SQUAMOUS-CELL CARCINOMA; CANCER-CELLS; DNA HYPERMETHYLATION; TUMOR-SUPPRESSOR; MIR-200; FAMILY; PANCREATIC-CANCER; BIOLOGICAL PROCESSES; COLORECTAL-CANCER; REPRESSORS ZEB1;
D O I
10.1371/journal.pone.0062757
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Recently, the epithelial-to-mesenchymal transition (EMT) has been demonstrated to contribute to normal and disease processes including cancer progression. To explore EMT-suppressive microRNAs (miRNAs), we established a cell-based reporter system using a stable clone derived from a pancreatic cancer cell line, Panc1, transfected with a reporter construct containing a promoter sequence of CDH1/E-cadherin in the 5' upstream region of the ZsGreen1 reporter gene. Then, we performed function-based screening with 470 synthetic double-stranded RNAs (dsRNAs) mimicking human mature miRNAs using the system and identified miR-655 as a novel EMT-suppressive miRNA. Overexpression of miR-655 not only induced the upregulation of E-cadherin and downregulation of typical EMT-inducers but also suppressed migration and invasion of mesenchymal-like cancer cells accompanied by a morphological shift toward the epithelial phenotype. In addition, we found a significant correlation between miR-655 expression and a better prognosis in esophageal squamous cell carcinoma (ESCC). Moreover, ZEB1 and TGFBR2, which are essential components of the TGF-b signaling pathway, were identified as direct targets of miR-655, suggesting that the activation of the TGF-b-ZEB1-E-cadherin axis by aberrant downregulation of miR-655 may accelerate cancer progression.
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页数:11
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