Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma

Isozaki,Yuka; Hoshino,Isamu; Nohata,Nijiro; Kinoshita,Takashi; Akutsu,Yasunori; Hanari,Naoyuki; Mori,Mikito; Yoneyama,Yasuo; Akanuma,Naoki; Takeshita,Nobuyoshi; Maruyama,Tetsuro; Seki,Naohiko; Nishino,Norikazu; Yoshida,Minoru; Matsubara,Hisahiro

doi:10.3892/ijo.2012.1537

September 2012 Volume 41 Issue 3

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September 2012 Volume 41 Issue 3

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Article

Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma

Authors:
- Yuka Isozaki
- Isamu Hoshino
- Nijiro Nohata
- Takashi Kinoshita
- Yasunori Akutsu
- Naoyuki Hanari
- Mikito Mori
- Yasuo Yoneyama
- Naoki Akanuma
- Nobuyoshi Takeshita
- Tetsuro Maruyama
- Naohiko Seki
- Norikazu Nishino
- Minoru Yoshida
- Hisahiro Matsubara
View Affiliations / Copyright

Affiliations: Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba, Japan, Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan, Graduate School of Life Sciences and Systems Engineering, Kyushu Institute of Technology, Wakamatsu-ku, Kitakyushu, Japan, Chemical Genetic Laboratory, RIKEN, Wako, Saitama, Japan
Pages: 985-994
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Published online on: June 28, 2012

https://doi.org/10.3892/ijo.2012.1537
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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.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma

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