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Mucosal microbiome associates with progression to gastric cancer.

ABSTRACT: Background & Aims: Dysbiosis is associated with gastric cancer (GC) development. However, no longitudinal study was carried out to identify key bacteria that could predict for GC progression. Here, we aimed to investigate changes in bacterial metagenome prior to GC and develop a microbiome-based predictive model to accurately classify patients at risk of GC. Methods: Bacterial 16S rDNA was sequenced from 89 gastric antral biopsies obtained from 43 participants. This study was nested in a prospective, longitudinal study, whereby study participants underwent screening gastroscopy, with further 1-2 yearly surveillance gastroscopies for at least 5 years. Putative bacterial taxonomic and functional features associated with GC carcinogenesis were identified by comparing between controls, patients with gastric intestinal metaplasia (IM) and patients with early gastric neoplasia (EGN). Results: Patients with EGN had enrichment of Proteobacteria (in particular Proteus genus) and depletion of Bacteroidetes (in particular S24-7 family) in their gastric mucosa. Sequencing identified more patients with Helicobacter pylori compared to histopathological assessment, while H. pylori was also significantly enriched in EGN. Furthermore, a total of 261 functional features, attributing to 97 KEGG pathways were differentially abundant at baseline between patients who subsequent developed EGN (n = 13/39) and those who did not. At the same time, a constellation of six microbial taxonomic features present at baseline, provided the highest classifying power for subsequent EGN (AUC = 0.82). Conclusion: Our study highlights early microbial changes associated with GC carcinogenesis, suggesting a potential role for prospective microbiome surveillance for GC.

SUBMITTER: Png CW

PROVIDER: S-EPMC8690935 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRing finger protein 43 (RNF43) is a member of the transmembrane E3 ubiquitin ligase family that was originally found in stem cells and plays important roles in tumor formation and progression. Our previous study indicated that RNF43 might be a tumor suppressor protein in gastric cancer. Given its antagonistic relationship with leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5), one of the gastric cancer stem cell markers, investigation of the potential role of RNF43 in gastric stem cancer cells is necessary.MethodsImmunohistochemistry staining, western blot analysis, and quantitative reverse transcription polymerase chain reaction were used to determine the mRNA and protein expression level of RNF43 and other Wnt pathway factors. Gastric cancer stem-like cells were obtained from gastric cancer tumor and cell lines by tumorsphere culture. The adeno-associated virus system was used to upregulate RNF43 expression in cancer cells. Functional experiments including tumorsphere formation, chemotherapy resistance, surface marker detection, and tumor xenograft assay were performed to measure stem-like properties in gastric cancer stem-like cells after RNF43 overexpression.ResultsRNF43 loss was significantly associated with TNM stage, distant metastasis, and Lauren classification, and predicted worse prognosis in gastric cancer patients. RNF43 expression was even lower in tumorspheres derived from tumor tissues or cell lines compared with adherent cancer cells and normal gastric cells. Overexpression of RNF43 in gastric cancer cells impaired their stem-like properties, including sphere formation ability, chemoresistance in vitro, and tumorigenicity in vivo. Moreover, Wnt pathway-related proteins were decreased in RNF43-overexpressing cells, while Wnt pathway activators could reverse the trend to some extent.ConclusionsOur findings indicated that RNF43 might not only participate in gastric cancer progression, but also attenuate the stemness of gastric cancer stem-like cells through the Wnt/β-catenin pathway.

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Mucosal microbiome associates with progression to gastric cancer.

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