Abstract
Gastric cancer (GC) is one of major global cancers that is highly heterogeneous and has a poor prognosis, especially in cases associated with Helicobacter pylori (H. pylori) infection. H. pylori promote metastasis via mechanisms like endoplasmic reticulum stress (ERS). Telomere-protecting protein 1 (TPP1), a telomere-protecting protein, is overexpressed in GC and linked to poor outcomes. This study investigated TPP1's role in H. pylori-induced ERS and its implications for GC metastasis.We analyzed TPP1 expression using both Starbase data and clinical samples. Functional assays (e.g., migration, invasion, wound healing) were performed in GC cell lines with TPP1 knockdown or overexpression. The interaction between TPP1 and ERS-related proteins was assessed by immunoprecipitation and immunofluorescence. The role of TPP1 in GC metastasis was further validated in a xenograft mouse model. TPP1 was upregulated in GC tissues and cell lines, correlating with poor prognosis. TPP1 knockdown inhibited GC cell metastasis but not proliferation, while TPP1 overexpression enhanced metastasis. H. pylori enhanced TPP1 expression by stabilizing Enhancer of Zeste Homolog 1, which in turn binds to the TPP1 promoter. TPP1 interacted with 78 kDa glucose-regulated protein, disrupting its binding to PKR-like ER kinase and activating ERS. Blocking ERS reversed the pro-metastatic effects of TPP1 overexpression. In vivo, TPP1 knockdown significantly reduced GC metastasis in nude mice xenograft model. TPP1, induced by H. pylori, promoted GC metastasis by enhancing ERS via interaction with glucose-regulated protein. Targeting the TPP1/ERS axis may offer a novel therapeutic strategy for GC.