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Original article
miR-30-HNF4γ and miR-194-NR2F2 regulatory networks contribute to the upregulation of metaplasia markers in the stomach
  1. Josane F Sousa1,
  2. Ki Taek Nam1,2,3,
  3. Christine P Petersen1,
  4. Hyuk-Joon Lee4,5,
  5. Han-Kwang Yang4,5,
  6. Woo Ho Kim6,
  7. James R Goldenring1
  1. 1Nashville VA Medical Center and the Epithelial Biology Center and Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  2. 2Severance Biomedical Science Institute, Seoul, Korea
  3. 3Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
  4. 4Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
  5. 5Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
  6. 6Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
  1. Correspondence to Dr James R Goldenring, Vanderbilt University School of Medicine, Section of Surgical Sciences, Epithelial Biology Center, 10435G MRB-IV, 2213 Garland Avenue, Nashville, TN 37232-2733, USA; jim.goldenring{at}vanderbilt.edu

Abstract

Objective Intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) are considered neoplastic precursors of gastric adenocarcinoma and are both marked by gene expression alterations in comparison to normal stomach. Since miRNAs are important regulators of gene expression, we sought to investigate the role of miRNAs on the development of stomach metaplasias.

Design We performed miRNA profiling using a quantitative reverse transcription-PCR approach on laser capture microdissected human intestinal metaplasia and SPEM. Data integration of the miRNA profile with a previous mRNA profile from the same samples was performed to detect potential miRNA-mRNA regulatory circuits. Transfection of gastric cancer cell lines with selected miRNA mimics and inhibitors was used to evaluate their effects on the expression of putative targets and additional metaplasia markers.

Results We identified several genes as potential targets of miRNAs altered during metaplasia progression. We showed evidence that HNF4γ (upregulated in intestinal metaplasia) is targeted by miR-30 and that miR-194 targets a known co-regulator of HNF4 activity, NR2F2 (downregulated in intestinal metaplasia). Intestinal metaplasia markers such as VIL1, TFF2 and TFF3 were downregulated after overexpression of miR-30a in a HNF4γ-dependent manner. In addition, overexpression of HNF4γ was sufficient to induce the expression of VIL1 and this effect was potentiated by downregulation of NR2F2.

Conclusions The interplay of the two transcription factors HNF4γ and NR2F2 and their coordinate regulation by miR-30 and miR-194, respectively, represent a miRNA to transcription factor network responsible for the expression of intestinal transcripts in stomach cell lineages during the development of intestinal metaplasia.

  • GASTRIC CANCER
  • GASTRIC ADENOCARCINOMA
  • GASTRIC EPITHELIAL CELL FUNCTION
  • GASTRIC METAPLASIA
  • GASTRIC PRE-CANCER

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