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miR-30-HNF4γ and miR-194-NR2F2 regulatory networks contribute to the upregulation of metaplasia markers in the stomach

Authors
 Josane F Sousa  ;  Ki Taek Nam  ;  Christine P Petersen  ;  Hyuk-Joon Lee  ;  Han-Kwang Yang  ;  Woo Ho Kim  ;  James R Goldenring 
Citation
 GUT, Vol.65(6) : 914-924, 2016 
Journal Title
 GUT 
ISSN
 0017-5749 
Issue Date
2016
MeSH
Adenocarcinoma/genetics ; Adenocarcinoma/pathology ; Biomarkers, Tumor/genetics* ; COUP Transcription Factor II/genetics ; Gastric Mucosa/pathology ; Gene Expression Regulation, Neoplastic ; Hepatocyte Nuclear Factor 4/genetics* ; Humans ; Metaplasia/genetics ; MicroRNAs/genetics* ; Microfilament Proteins/genetics ; Peptides/genetics ; Stomach/pathology ; Stomach Neoplasms/genetics ; Stomach Neoplasms/pathology ; Transfection ; Trefoil Factor-2/genetics ; Trefoil Factor-3/genetics ; Up-Regulation/genetics*
Keywords
GASTRIC ADENOCARCINOMA ; GASTRIC CANCER ; GASTRIC EPITHELIAL CELL FUNCTION ; GASTRIC METAPLASIA ; GASTRIC PRE-CANCER
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.
Full Text
http://gut.bmj.com/content/65/6/914
DOI
10.1136/gutjnl-2014-308759
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Nam, Ki Taek(남기택)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146938
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