title: miR-655 Is an EMT-suppressive microRNA targeting ZEB1 and TGFBR2.
abstract: 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.
authors.affiliation: Department of Molecular Cytogenetics, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Harazono
authors.forename: Tomoki
authors.initials: T
authors.lastname: Muramatsu
authors.forename: Hironori
authors.initials: H
authors.lastname: Endo
authors.forename: Narikazu
authors.initials: N
authors.lastname: Uzawa
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Kawano
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Harada
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kozaki
mesh_terms: D015703:Antigens, CD; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D009062:Mouth Neoplasms / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; C585264:MIRN655 microRNA, human; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II