Abstract
Helicobacter pylori infection, the main risk factor for gastric cancer (GC), leads to an epithelial–mesenchymal transition (EMT) of gastric epithelium contributing to gastric cancer stem cell (CSC) emergence. The Hippo pathway effectors yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) control cancer initiation and progression in many cancers including GC. Here, we investigated the role of TAZ in the early steps of H. pylori-mediated gastric carcinogenesis. TAZ implication in EMT, invasion, and CSC-related tumorigenic properties were evaluated in three gastric epithelial cell lines infected by H. pylori. We showed that H. pylori infection increased TAZ nuclear expression and transcriptional enhancer TEA domain (TEAD) transcription factors transcriptional activity. Nuclear TAZ and zinc finger E-box-binding homeobox 1 (ZEB1) were co-overexpressed in cells harboring a mesenchymal phenotype in vitro, and in areas of regenerative hyperplasia in gastric mucosa of H. pylori-infected patients and experimentally infected mice, as well as at the invasive front of gastric carcinoma. TAZ silencing reduced ZEB1 expression and EMT phenotype, and strongly inhibited invasion and tumorsphere formation induced by H. pylori. In conclusion, TAZ activation in response to H. pylori infection contributes to H. pylori-induced EMT, invasion, and CSC-like tumorigenic properties. TAZ overexpression in H. pylori-induced pre-neoplastic lesions and in GC could therefore constitute a biomarker of early transformation in gastric carcinogenesis.
Highlights
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide [1,2]
Kinetics of transcriptional co-activator with PDZ binding motif (TAZ) protein expression and TAZ/yes-associated protein (YAP)-mediated TEA domain (TEAD) transcriptional activity were performed in these three gastric cell lines in response to infection with the cytotoxin associated gene A (cagA)-positive 7.13 wild type (WT) H. pylori strain (Figure 1C,D)
The results showed that H. pylori stimulated both TAZ protein infection, TEAD transcriptional activity remained upregulated in MKN45 but repressed in GC07 cells and to a lesser extent in NCI-N87
Summary
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide [1,2]. GCs are mostly non-cardia gastric adenocarcinomas, occurring in patients around 70 years old. GC has an infectious origin, attributed to the infection by the bacterium Helicobacter pylori. Half of the world’s population is infected with H. pylori, and this infection is detected in more than 92% GC cases [3,4]. Infection with H. pylori always leads to chronic inflammation of the gastric mucosa, which can potentially evolve slowly into atrophy, metaplasia, and dysplasia, and in the worst scenario leads to non-cardia gastric carcinoma after several decades [5]. The major H. pylori virulence factor is carried by the cag pathogenicity island (cagPAI), which encodes a type 4 secretion system (T4SS)
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