Abstract
Gastric cancer is the most common gastrointestinal tumor with an increasing incidence. Furthermore, advanced gastric cancer is more common, but the mechanism underlying the proliferation and metastasis of gastric cancer has not been thoroughly explored. N6-methyladenosine (m6A) methyltransferase 3 (METTL3) may be involved in the proliferation and metastasis of gastric cancer. Therefore, Yes-associated protein 1 (YAP1) in the Hippo pathway was selected as the target, and the relationship between METTL3 and the proliferation and metastasis of gastric cancer was proved through a series of experiments. This research showed that the expression of m6A and METTL3 was upregulated in human gastric cancer tissues and gastric cancer cell lines. After lentiviral transfection, METTL3 silencing in AGS (human gastric adenocarcinoma cell line AGS) and MKN-45 (human gastric cancer cell line MKN-45) gastric cancer cell lines directly inhibited the proliferation, aggressiveness, and migration of gastric cancer cells. Mechanically, the inhibition of the YAP1-TEAD signaling pathway by peptide 17 reduces m6A methylation and the total mRNA level of YAP1. It also eliminates the promoting effect of METTL3 on the proliferation and migration of gastric cancer cells. In turn, the overexpression of YAP1 eliminates the inhibitory effect of METTL3 silencing on the proliferation, migration, and invasion of gastric cancer cells. This article proved that m6A methyltransferase METTL3 promoted the proliferation and migration of gastric cancer cells through the m6A modification of YAP1.
Highlights
Gastric cancer has become the most common gastrointestinal tumor with increased morbidity and mortality, ranking fourth in the global incidence of cancer [1]
Abnormal DNA methylation is caused by specific inflammation and may be related to the expression of interleukin-1beta (Il1b), nitric oxide synthase2 (Nos2), and tumor necrosis factor (Tnf ), while the inactivation of tumor suppressor genes, such as P16, hMLH1, and CDH1, and the activation of the Wnt pathway may be caused by abnormal DNA methylation [4]. e progression of gastric cancer is Journal of Oncology closely related to the imbalance of methylation
The expression of m6A was significantly higher in gastric cancer tissues than in normal tissues. e detection of mRNA levels of m6A-modified enzymes (METTL3, Wilms tumor 1-related proteins (WTAP), METTL14, VIRMA, RNA-binding motif protein-15 (RBM15), fat-mass- and obesity-related protein (FTO), and ALKBH5) in gastric cancer tissues and adjacent tissues showed that the mRNA level of METTL3 was significantly higher in gastric cancer tissues
Summary
Gastric cancer has become the most common gastrointestinal tumor with increased morbidity and mortality, ranking fourth in the global incidence of cancer [1]. Gastric cancer is the result of a combination of many factors. Some relevant studies have suggested a relation of gastric cancer with the malignant transformation of Helicobacter pylori, environment, genes, high-salt diet, and even stem cells on the mucosal surface of gastric cancer cells [2]. It is more apt to say that the inflammatory response induced by H. pylori directly leads to DNA methylation, but not all kinds of inflammation induce abnormalities in DNA. Abnormal DNA methylation is caused by specific inflammation and may be related to the expression of interleukin-1beta (Il1b), nitric oxide synthase (Nos2), and tumor necrosis factor (Tnf ), while the inactivation of tumor suppressor genes, such as P16, hMLH1, and CDH1, and the activation of the Wnt (wingless/integrated) pathway may be caused by abnormal DNA methylation [4]. Abnormal DNA methylation is caused by specific inflammation and may be related to the expression of interleukin-1beta (Il1b), nitric oxide synthase (Nos2), and tumor necrosis factor (Tnf ), while the inactivation of tumor suppressor genes, such as P16, hMLH1, and CDH1, and the activation of the Wnt (wingless/integrated) pathway may be caused by abnormal DNA methylation [4]. e progression of gastric cancer is
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