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

SIMPLE SUMMARY: The members of the TFF family have been illustrated to be tumor suppressor genes in various malignancies. In this study, we first identified that TFF1/TFF2 expressions were mediated by DNA methylation in gastric cancer. Moreover, the specific CpG island sites of TFF1/TFF2, which corresponded to the downregulation of these two genes, were also discovered through integrative analysis. In addition, using the gain of function assay, it was found out that TFF1 and TFF2 could suppress the pathogenesis of gastric cancer. Totally, TFF1 and TFF2 could be the potential DNA methylation biomarkers for 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.