RRC ID 65139
Author Shao L, Chen Z, Peng D, Soutto M, Zhu S, Bates A, Zhang S, El-Rifai W.
Title Methylation of the HOXA10 Promoter Directs miR-196b-5p-Dependent Cell Proliferation and Invasion of Gastric Cancer Cells.
Journal Mol Cancer Res
Abstract The cross-talk between epigenetics and miRNA 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 and miR-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. ©2018 AACR.
Volume 16(4)
Pages 696-706
Published 2018-4-1
DOI 10.1158/1541-7786.MCR-17-0655
PII 1541-7786.MCR-17-0655
PMID 29453320
PMC PMC5882501
MeSH Animals Cell Line, Tumor Cell Proliferation / drug effects DNA Methylation* / drug effects Decitabine / pharmacology Epigenesis, Genetic Gene Expression Regulation, Neoplastic / drug effects Homeobox A10 Proteins Homeodomain Proteins / genetics* Humans Mice Mice, Knockout MicroRNAs / genetics* Neoplasm Invasiveness Prognosis Promoter Regions, Genetic / drug effects Stomach Neoplasms / genetics* Survival Analysis Trefoil Factor-1 / genetics* Up-Regulation* / drug effects
IF 4.63
Human and Animal Cells MKN45(RCB1001)