title: MiR-150 is associated with poor prognosis in esophageal squamous cell carcinoma via targeting the EMT inducer ZEB1.
abstract: The association of microRNAs (miRs) with cancer progression has been established in many cancers including esophageal squamous cell carcinoma (ESCC). A public microarray database showed that the expression of miR-150 was lower in ESCC than in normal esophageal mucosa. Here, we focused on ZEB1, epithelial-mesenchymal-transition (EMT)-inducer, as a target gene of miR-150 based on in silico predictions. The purpose of this study was to clarify the clinicopathological significance of miR-150 in ESCC, and to investigate miR-150's EMT-regulatory ability. Quantitative RT-PCR was used to evaluate miR-150 expression in 108 curative resected ESCC samples to determine the clinicopathological significance. Moreover, we examined the in vitro and in vivo function of miR-150 via degradation of ZEB1. MiR-150 expression was significantly lower in cancer tissues compared to adjacent non-cancerous tissues (P < 0.001). Low expression of miR-150 in ESCC contributed to malignant potential, such as tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, clinical staging, and poor prognosis (P < 0.05). In vitro assays showed that EMT-inducer-ZEB1 is a new direct target of miR-150. Moreover, miR-150 induced MET-like changes in TE-8 cells through ZEB1 degradation (e.g., E-cadherin expression, vimentin repression, epithelial morphology, and suppression of migration ability), and significantly inhibited tumorigenicity and tumor growth in a mouse xenograft model. Analysis of the regulation of ZEB1 by miR-150 could provide new insights into preventing metastasis and also suggests novel targeted therapeutic strategies in ESCC.
authors.affiliation: Department of General Surgical Science, Gunma University, Graduate School of Medicine, Maebashi, Gunma, Japan. bori45@gunma-u.ac.jp
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokobori
authors.forename: Shigemasa
authors.initials: S
authors.lastname: Suzuki
authors.forename: Naritaka
authors.initials: N
authors.lastname: Tanaka
authors.forename: Takanori
authors.initials: T
authors.lastname: Inose
authors.forename: Makoto
authors.initials: M
authors.lastname: Sohda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sano
authors.forename: Makoto
authors.initials: M
authors.lastname: Sakai
authors.forename: Masanobu
authors.initials: M
authors.lastname: Nakajima
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D015820:Cadherins / Q000096:biosynthesis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014746:Vimentin / Q000096:biosynthesis; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D014157:Transcription Factors; D014746:Vimentin; D000071799:Zinc Finger E-box-Binding Homeobox 1; C533097:MIR150, human; C486307:ZEB1 protein, human