Validation of the DNA Methylation Landscape of TFF1/TFF2 in Gastric Cancer

Abstract

As one of the most frequently occurring tumor types, the increasing incidence of gastric cancer (GC) has been observed in the past decades. The recent studies have illustrated that epigenetic modifications mediated by DNA methyltransferases (DNMTs) are the major epigenetic hallmark in GC progression. Nowadays, DNA methylation was considered to be necessary for inducing the silence of tumor suppressor genes (TSGs). As an important group of peptides, the TFF family has been confirmed to function as a TSG in various kinds of cancers. However, whether TFFs could be modified by DNA methylation in gastric cancer remains unknown. Here, we initially screened out two transcriptional sequencing profiles about GC from Gene Expression Omnibus (GEO) database. The lower expression levels of TFF1 and TFF2 were observed in GC tumor tissues as compared to those in normal tissues. Additionally, utilizing the Kaplan–Meier analysis, the expressions of TFF1 and TFF2 were identified to be associated with the prognosis of GC patients. Subsequently, the integrative analysis was performed to estimate the DNA methylation level of each site in TFF1/TFF2 CpG islands. Importantly, our findings indicated that hyper-methylation of cg01886855 and cg26403416 were separately responsible for the downregulation of TFF1 and TFF2 in GC samples. In addition, utilizing the experiments in vitro, we demonstrated that TFF1/TFF2 could suppress the proliferation of GC cells. Based on these results, we suspected that TFF1/TFF2 could potentially act as the putative tumor suppressor in GC, and these two TFFs were of great value for predicting the overall survival (OS) status in the gastric cancer cohort. Totally, our findings revealed a potential therapeutic method for targeting the TFFs for the treatment of GC.

The EBV Gastric Cancer Resource (EBV-GCR): A Suite of Tools for Investigating EBV-Associated Human Gastric Carcinogenesis

“…Multiple reports indicate that TFF1 expression is downregulated by the EBV infection of AGS or MKN7 gastric cells [54][55][56]. TFF1 mRNA levels were similarly reduced in non-TCGA cohort-based EBVaGC samples compared to their EBVnGC counterparts [57]. Using the differential gene expression tool for EBV-GCR, a similar, statistically significant downregulation of TFF1 expression was also observed in the TCGA bulk sequencing data (Figure 6A).…”

“…Using the differential gene expression tool for EBV-GCR, a similar, statistically significant downregulation of TFF1 expression was also observed in the TCGA bulk sequencing data (Figure 6A). Both cell culture infection models and non-TCGA cohort EBVaGC data have identified increased methylation of the TFF1 gene in the presence of EBV [54,57]. The methylation and silencing can be reversed by 5-aza−2 -deoxycytidine treatment in culture, suggesting that EBV-induced hypermethylation is important for this repression [54].…”

A Genotype-Phenotype Model for Predicting Resistance Training Effects on Leg Press Performance

“…TFF1 was first identified in the MCF-7 breast cancer cell line, and its full gene sequence was subsequently cloned [66]. Since then, numerous studies have found abnormal expression of TFF family proteins (mainly TFF1 and TFF3) in various solid tumors [67][68][69]. Research has shown that TFF2 is associated with energy metabolism and can regulate skeletal muscle mass.…”

The Role of Mucin Expression in the Diagnosis of Oesophago-Gastric Cancer: A Systematic Literature Review

“…In their study, Ge et al reported that MUC1 is associated with the methylation of trefoil factor family 2 (TFF2), a secreted peptide that promotes epithelial repair, in Helicobacter pylori-infected gastric cells [55]. However, the mechanism through which this occurs is yet to be elucidated [57]. Furthermore, aberrant MUC1, following H. pylori infection regulates the methylation status of TFF2, thus contributing to the silencing of this peptide, leading towards GC development [57].…”

“…However, the mechanism through which this occurs is yet to be elucidated [57]. Furthermore, aberrant MUC1, following H. pylori infection regulates the methylation status of TFF2, thus contributing to the silencing of this peptide, leading towards GC development [57]. A further study by Shi et al identified that the methylation of the promoter region in the MUC6 gene leads to the downregulation of MUC6 expression, which may promote the metastasis of GC [58].…”