Methylation of the HOXA10 promoter directs miR-196b-5p-dependent cell proliferation and invasion of gastric cancer cells

Linlin Shao, Zheng Chen, Dunfa Peng, Mohammed Soutto, Shoumin Zhu, Andreia Bates, Shutian Zhang, Wael El-Rifai

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

The cross-talk between epigenetics andmiRNA expression plays an important role in human tumorigenesis. Herein, the regulation and role of miR-196b-5p in gastric cancer was investigated. qRT-PCR demonstrated that miR-196b-5p is significantly overexpressed in human gastric cancer tissues (P < 0.01). In addition, it was determined that HOXA10, a homeobox family member and host gene for miR-196b-5p, is overexpressed and positively correlated with miR-196b-5p expression levels (P < 0.001). Quantitative pyrosequencing methylation analysis demonstrated significantly lower levels of DNA methylation at the HOXA10 promoter in gastric cancer, as compared with nonneoplastic gastric mucosa specimens. 5-Aza-2′-deoxycytidine treatment confirmed that demethylation of HOXA10 promoter induces the expression of HOXA10 and miR-196b-5p in gastric cancer cell model systems. Using the Tff1 knockout mouse model of gastric neoplasia, hypomethylation and overexpression of HOXA10 and miR-196b-5p in gastric tumors was observed, as compared with normal gastric mucosa from Tff1 wild-type mice. Mechanistically, reconstitution of TFF1 in human gastric cancer cells led to an increased HOXA10 promoter methylation with reduced expression of HOXA10 andmiR-196b-5p. Functionally, miR-196b-5p reconstitution promoted human gastric cancer cell proliferation and invasion in vitro. In summary, the current data demonstrate overexpression of miR-196b-5p in gastric cancer and suggest that TFF1 plays an important role in suppressing the expression of miR-196b-5p by mediating DNA methylation of the HOXA10 promoter. Loss of TFF1 expression may promote proliferation and invasion of gastric cancer cells through induction of promoter hypomethylation and expression of the HOXA10/miR-196b-5p axis. Implications: This study indicates that loss of TFF1 promotes the aberrant overexpression of HOXA10 and miR-196b-5p by demethylation of the HOXA10 promoter, which provides a new perspective of TFF1/HOXA10/miR-196b-5p functions in human gastric cancer. Mol Cancer Res; 16(4); 696-706.

Original languageEnglish (US)
Pages (from-to)696-706
Number of pages11
JournalMolecular Cancer Research
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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