title: Identification of novel molecular targets regulated by tumor suppressive             miR-375 induced by histone acetylation in esophageal squamous cell carcinoma.
abstract: The aim of this study was to determine whether histone acetylation regulates             tumor suppressive microRNAs (miRNAs) in esophageal squamous cell carcinoma (ESCC)             and to identify genes which are regulated by these miRNAs. We identified a miRNA             that was highly upregulated in an ESCC cell line by cyclic hydroxamic acid-containing             peptide 31 (CHAP31), one of the histone deacetylase inhibitors (HDACIs), using             a miRNA array analysis. miR-375 was strongly upregulated by CHAP31 treatment in             an ESCC cell line. The expression levels of the most upregulated miRNA, miR-375             were analyzed by quantitative real-time PCR in human ESCC specimens. The tumor             suppressive function of miR-375 was revealed by restoration of miR-375 in ESCC             cell lines. We performed a microarray analysis to identify target genes of miR-375.             The mRNA and protein expression levels of these genes were verified in ESCC clinical             specimens. LDHB and AEG-1/MTDH were detected as miR‑375-targeted genes. The restoration             of miR-375 suppressed the expression of LDHB and AEG-1/MTDH. The ESCC clinical             specimens exhibited a high level of LDHB expression at both the mRNA and protein             levels. A loss-of-function assay using a siRNA analysis was performed to examine             the oncogenic function of the gene. Knockdown of LDHB by RNAi showed a tumor suppressive             function in the ESCC cells. The correlation between gene expression and clinicopathological             features was investigated by immunohistochemistry for 94 cases of ESCC. The positive             staining of LDHB correlated significantly with lymph node metastasis and tumor             stage. It also had a tendency to be associated with a poor prognosis. Our results             indicate that HDACIs upregulate miRNAs, at least some of which act as tumor suppressors.             LDHB, which is regulated by the tumor suppressive miR-375, may therefore act as             an oncogene in ESCC.
authors: Department of Frontier Surgery, Chiba University Graduate School                     of Medicine, Chiba, Japan.
authors: Yuka
authors: Y
authors: Isozaki
authors: Isamu
authors: I
authors: Hoshino
authors: Nijiro
authors: N
authors: Nohata
authors: Takashi
authors: T
authors: Kinoshita
authors: Yasunori
authors: Y
authors: Akutsu
authors: Naoyuki
authors: N
authors: Hanari
authors: Mikito
authors: M
authors: Mori
authors: Yasuo
authors: Y
authors: Yoneyama
authors: Naoki
authors: N
authors: Akanuma
authors: Nobuyoshi
authors: N
authors: Takeshita
authors: Tetsuro
authors: T
authors: Maruyama
authors: Naohiko
authors: N
authors: Seki
authors: Norikazu
authors: N
authors: Nishino
authors: Minoru
authors: M
authors: Yoshida
authors: Hisahiro
authors: H
authors: Matsubara
mesh_terms: D000107:Acetylation; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010456:Peptides, Cyclic / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007527:Isoenzymes; C540933:MIRN375 microRNA, human; C483039:MTDH protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D010456:Peptides, Cyclic; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C505396:cyclic hydroxamic acid-containing peptide 31; D007770:L-Lactate Dehydrogenase; C409667:lactate dehydrogenase 1