YTHDF2 Inhibits Gastric Cancer Cell Growth by Regulating FOXC2 Signaling Pathway

Abstract

BackgroundGastric cancer (GC) is one of the most common malignancies in the world, and the fourth most frequent malignancy worldwide. YTHDF2 (YTH domain family 2, YTHDF2) binds to mRNA containing m6A, thereby regulating the localization and stability of the bound mRNA. YTHDF2 was shown to be associated with some cancer patient prognosis. However, the effect of YTHDF2 on gastric cancer and the molecular mechanism of this effect have not been documented.MethodsTo conduct this research, YTHDF2 expression levels in public databases and gastric cancer patient samples were analyzed. The effects of YTHDF2 on the growth of gastric cancer cells were detected in vivo and in vitro. RNA-seq was used to analyze the signal pathways regulated by YTHDF2, and experiments were carried out for verification.ResultsIn our study, we found that YTHDF2 has lower expression in GC tissues and GC cells, and inhibits the growth of GC cells. In addition, the analysis of clinical data found that the expression level of YTHDF2 is closely related to the stage of GC and the survival of patients with GC. RNA sequencing results showed that overexpression of YTHDF2 significantly reduced protein expression in the FOXC2 (Forkhead box protein C2, FOXC2) signaling pathway. Finally, we found that knockout of FOXC2 reversed the inhibitory effect of YTHDF2 on GC cells.ConclusionIn summary, YTHDF2 inhibits the growth of GC cells by negatively regulating FOXC2 and may serve as a prognostic marker in GC.

Comprehensive Analysis of the Prognostic Role and Mutational Characteristics of m6A-Related Genes in Lung Squamous Cell Carcinoma

“…According to the characteristics of m6A proteins, they are divided as "writer, " "eraser, " and "reader" proteins, which dynamically regulate tumor-related pathological and physiological functions (Gu et al, 2020b). Many previous researches have proved the effects of N6-methyladenosine (m6A) RNA modification and its ability to regulate and coordinate related gene expression, whose level will profoundly affect cancer characteristics (Gu et al, 2020b;Shen et al, 2020;Wei et al, 2020). For example, in lung cancer, METTL3 acts as an oncogene, which increases the growth, survival, and invasion of lung adenocarcinoma cells (Lin et al, 2016).…”

Comprehensive Analysis of the Immune Infiltrates and PD-L1 of m6A RNA Methylation Regulators in Hepatocellular Carcinoma

“…YTHDF1 and its m 6 A-mediated regulation of Wnt/β-catenin signaling promote gastric cancer progression. METTL3-mediated m 6 A modification facilitates gastric cancer progression and has poor prognosis ( Pi et al, 2020 ; Shen et al, 2020 ; Wang Q. et al, 2020 ). Also, HNRNPC and YTHDF1 have an effect on prognosis in breast cancer patients ( Wu et al, 2018 ; Anita et al, 2020 ).…”

The m6A RNA Modification Quantity and mRNA Expression Level of RNA Methylation-Related Genes in Head and Neck Squamous Cell Carcinoma Cell Lines and Patients

“…YTHDF2 binding to m 6 A promotes RNA decay, while YTHDC2 is involved in mRNA degradation and translation initiation. These regulators were demonstrated to play a crucial role in a variety types of cancers [ 21 , 30 , 31 , 32 ]. The role of the YTHDF2 gene in HNSCC has not been explored so far, whereas YTHDC2 was found to be a tumor suppressor with low expression in HNSCC samples, while its upregulation was associated with longer-term survival and the recurrence-free survival of HNSCC patients [ 33 ].…”