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

Josane F. Sousa, Ki Taek Nam, Christine P. Petersen, Hyuk Joon Lee, Han Kwang Yang, Woo Ho Kim, James R. Goldenring

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)914-924
Number of pages11
Issue number6
Publication statusPublished - 2016 Jun 1

Bibliographical note

Funding Information:
These studies were supported by grants to JRG from NIH RO1 DK071590, ARRA Supplemental Funding from RO1 DK071590-S1, from CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences, a Veterans Affairs Merit Review I01BX000930 and from a grant from the T.J. Martell Foundation. JFS was supported by a fellowship from the Prevent Cancer Foundation. This work was supported by core resources of the Vanderbilt Digestive Disease Center (P30 DK058404), and the Vanderbilt-Ingram Cancer Center through NCI Cancer Center Support Grant P30 CA068485 using the Translational Pathology Shared Resource.

Publisher Copyright:
© 2016, BMJ Publishing Group. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Gastroenterology


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