Abstract
Gastric cancer (GC) has a high mortality rate, and metastasis is the main reason for treatment failure. It is important to study the mechanism of tumour invasion and metastasis based on the regulation of key genes. In a previous study comparing the expression differences between GES-1 and SGC-7901 cells, PCDHGA9 was selected for further research. In vitro and in vivo experiments showed that PCDHGA9 inhibited invasion and metastasis. A cluster analysis suggested that PCDHGA9 inhibited epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin and TGF-β pathways. Laser confocal techniques and western blotting revealed that PCDHGA9 inhibited the nuclear translocation of β-catenin, regulated T cell factor (TCF)/ /lymphoid enhancer factor (LEF) transcriptional activity, directly impacted the signal transmission of the TGF-β/Smad2/3 pathway, strengthened the adhesion complex, weakened the effects of TGF-β, and blocked the activation of the Wnt pathway. In addition, PCDHGA9 expression was regulated by methylation, which was closely related to poor clinical prognosis. The aim of this study was to elucidate the molecular mechanism by which PCDHGA9 inhibits EMT and metastasis in GC to provide a new theoretical basis for identifying GC metastasis and a new target for improving the outcome of metastatic GC.
Highlights
Gastric cancer (GC) was the second leading cause of cancer-related death and the sixth most frequently diagnosed cancer worldwide in 20181
We clearly demonstrated that PCDHGA9 suppresses GC cell proliferation via the Wnt/β-catenin pathway and inhibits Epithelial-mesenchymal transition (EMT) by suppressing transforming growth factor-β (TGF-β)/Smad2/3 pathway activation
We further determined that PCDHGA9 could directly interact with β-catenin to form a complex at the GC cell membrane to inhibit EMT, and we provide evidence of the association between the canonical Wnt pathway and the TGF-β pathway
Summary
Gastric cancer (GC) was the second leading cause of cancer-related death and the sixth most frequently diagnosed cancer worldwide in 20181. Tumour metastasis is a multistep and multi-molecular process[4]; a thorough understanding of the mechanism underlying. Epithelial cells undergo a developmental switch that enables them to acquire mesenchymal characteristics, resulting in a decrease in adhesion and cell polarity and an increase in motility and invasiveness during EMT6. This process is associated with upregulation of N-cadherin, Vimentin and Slug and concomitant downregulation of E-cadherin[7]. EMT involves complex mechanisms regulated by many signalling pathways, including the Wnt/ β-catenin pathway, the transforming growth factor-β (TGF-β)/Smad2/3 pathway and other pathways[8,9]. Accumulating evidence indicates that the canonical Wnt pathway negatively regulates E-cadherin and induces
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