title: The downregulation of miR-200c/141 promotes ZEB1/2 expression and gastric cancer progression.
abstract: Gastric cancer is the fourth most common malignancy in the world. Although microRNA-200 (miR-200) family members are thought to play roles in tumorigenesis, their functions in carcinogenesis are tumor specific, and the underlying mechanism of action still remains elusive. Few studies to date have addressed the dysregulation and function of miR-200 family members in gastric cancer progression. Here, we report that the miR-200 family members, miR-200c and miR-141, were significantly downregulated in gastric cancer specimens and gastric cancer cell lines. Importantly, on clinical samples, the expression of miR-200c and miR-141 was inversely correlated with TNM stage, tumor invasion depth (T), tumor embolus and disease-free survival. Wound-healing assay results showed that co-transfected miR-200c/141 could inhibit the migration and invasion capability of the gastric cell line SGC-7901. We also found that miR-200c and miR-141 directly targeted zinc finger E-box-binding homeobox 1/2 (ZEB1/2) and upregulated E-cadherin expression. In specimens from gastric cancer patients, reduced expression of miR-200c/141 was associated with increased expression of ZEB1 and/or ZEB2. In addition, the downregulation of miR-200c and miR-141 was found to be due to a highly methylated CpG island located upstream of their genomic sequence and/or upregulated TGF-β signaling. Treatment with the chemotherapeutic agent decitabine, a known DNA methyltransferase inhibitor, increased miR-200c/141 expression and ameliorated decreased expression of miR-200c/141 induced by TGF-β in SGC-7901 cells. Our study revealed that miR-200c/141 was downregulated by CpG island methylation and TGF-β signaling, which decreased ZEB1/2 expression and increased E-cadherin expression to inhibit migration and invasion of gastric cancer cells and provides powerful evidence for the application of decitabine in gastric cancer treatment.
authors.affiliation: Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, People's Republic of China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Zhou
authors.forename: Yudong
authors.initials: Y
authors.lastname: Wang
authors.forename: Baoen
authors.initials: B
authors.lastname: Shan
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhu
authors.forename: Yalei
authors.initials: Y
authors.lastname: Lv
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Fan
authors.forename: Meixiang
authors.initials: M
authors.lastname: Sang
authors.forename: Xian-De
authors.initials: XD
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
mesh_terms: D000368:Aged; D015153:Blotting, Western; D002465:Cell Movement / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D018398:Homeodomain Proteins; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1