title: miR-145, miR-133a and miR-133b: Tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma.
abstract: MicroRNAs (miRNAs), noncoding RNAs 21-25 nucleotides in length, regulate gene expression primarily at the posttranscriptional level. Growing evidence suggests that miRNAs are aberrantly expressed in many human cancers, and that they play significant roles in carcinogenesis and cancer progression. A search for miRNAs with a tumor-suppressive function in esophageal squamous cell carcinoma (ESCC) was performed using the miRNA expression signatures obtained from ESCC clinical specimens. A subset of 15 miRNAs was significantly downregulated in ESCC. A comparison of miRNA signatures from ESCC and our previous report identified 4 miRNAs that are downregulated in common (miR-145, miR-30a-3p, miR-133a and miR-133b), suggesting that these miRNAs are candidate tumor suppressors. Gain-of-function analysis revealed that 3 transfectants (miR-145, miR-133a and miR-133b) inhibit cell proliferation and cell invasion in ESCC cells. These miRNAs (miR-145, miR-133a and miR-133b), which have conserved sequences in the 3'UTR of FSCN1 (actin-binding protein, Fascin homolog 1), inhibited FSCN1 expression. The signal from a luciferase reporter assay was significantly decreased at 2 miR-145 target sites and 1 miR-133a/b site, suggesting both miRNAs directly regulate FSCN1. An FSCN1 loss-of-function assay found significant cell growth and invasion inhibition, implying an FSCN1 is associated with ESCC carcinogenesis. The identification of tumor-suppressive miRNAs, miR-145, miR-133a and miR-133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis.
authors.affiliation: Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kano
authors.forename: Naohiko
authors.initials: N
authors.lastname: Seki
authors.forename: Naoko
authors.initials: N
authors.lastname: Kikkawa
authors.forename: Lisa
authors.initials: L
authors.lastname: Fujimura
authors.forename: Isamu
authors.initials: I
authors.lastname: Hoshino
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Akutsu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyomaru
authors.forename: Hideki
authors.initials: H
authors.lastname: Enokida
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Matsubara
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C502658:FSCN1 protein, human; C548234:MIRN133 microRNA, human; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D008840:Microfilament Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D008156:Luciferases