Methylation of the HOXA10 Promoter Directs miR-196b-5p–Dependent Cell Proliferation and Invasion of Gastric Cancer Cells

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. Quantitative real-time RT-PCR (qPCR) 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 to non-neoplastic 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-KO mouse model of gastric neoplasia, hypo-methylation and overexpression of HOXA10 and miR-196b-5p in gastric tumors was observed, as compared to normal gastric mucosa from Tff1-WT mice. Mechanistically, reconstitution of TFF1 in human gastric cancer cells lead 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 demonstrates overexpression of miR-196b-5p in gastric cancer and suggests 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 hypo-methylation and expression of the HOXA10/miR-196b-5p axis.

A network-based approach to identify DNA methylation and its involved molecular pathways in testicular germ cell tumors

“…DNA methylation is reported to lead to gene silencing via inhibiting gene transcription, which has become the most studied epigenetic mechanism [7]. Accumulated studies have showed that aberrant methylation of gene promoter regions is associated with occurrence, progression, and metastasis of several tumors, including ovarian carcinoma [8], gastric cancer [9] and so on. The profile of gene promoter methylation in TGCT was reported by several studies [10][11][12].…”

Up-regulated Linc00472 suppresses development of lung cancer cell via inhibition of MiR-196b-5p

“…MicroRNAs (miRNAs) are a class of small endogenous non-coding genes with~22 nucleotides that exert pivotal roles in post-transcriptional regulation and different biological processes, especially in the progression of cancer [11]. MiR-196b-5p is involved in the progression of several cancers, such as colorectal cancer [12], gastric cancer [13,14]. However, very little is revealed about the role of miR-196b-5p in LC.…”

CircCTDP1 promotes nasopharyngeal carcinoma progression via a microRNA‑320b/HOXA10/TGFβ2 pathway

“…HOX genes are divided into 4 groups (HOXA, HOXB, HOXC and HOXD) encode transcription factors involved in the control of cell growth (41,42). It has been reported that HOXA10 is associated with cell migration, proliferation and survival in various types of cancer (43,44). In the current study, it was demonstrated that HOXA10 was a direct downstream target of miR-320b through bioinformatic prediction and in vitro experiments, and overexpression of HOXA10 was found to promote the progression and development of NPc cells.…”