Transcriptomic and Metabolomic Profiling in Helicobacter pylori-Induced Gastric Cancer Identified Prognosis- and Immunotherapy-Relevant Gene Signatures.

Duanrui Liu,Yufei Wu,Yanfei Jia,Xiaoli Ma,Yuanxin Xing,Yunshan Wang,Jingyu Zhu,Lulu Zhang,Wenshuai Zhu

doi:10.3389/fcell.2021.769409

Abstract

Background: Chronic Helicobacter pylori (HP) infection is considered the major cause of non-cardia gastric cancer (GC). However, how HP infection influences the metabolism and further regulates the progression of GC remains unknown. Methods: We comprehensively evaluated the metabolic pattern of HP-positive (HP+) GC samples using transcriptomic data and correlated these patterns with tumor microenvironment (TME)–infiltrating characteristics. The metabolic score was constructed to quantify metabolic patterns of individual tumors using principal component analysis (PCA) algorithms. The expression alterations of key metabolism-related genes (MRGs) and downstream metabolites were validated by PCR and untargeted metabolomics analysis. Results: Two distinct metabolic patterns and differential metabolic scores were identified in HP+ GC, which had various biological pathways in common and were associated with clinical outcomes. TME-infiltrating profiles under both patterns were highly consistent with the immunophenotype. Furthermore, the analysis indicated that a low metabolic score was correlated with an increased EMT subtype, immunosuppression status, and worse survival. Importantly, we identified that the expression of five MRGs, GSS, GMPPA, OGDH, SGPP2, and PIK3CA, was remarkably correlated with HP infection, patient survival, and therapy response. Furthermore, the carbohydrate metabolism and citric acid may be downstream regulators of the function of metabolic genes in HP-induced GC. Conclusion: Our findings suggest that there is cross talk between metabolism and immune promotion during HP infection. MRG-specific transcriptional alterations may serve as predictive biomarkers of survival outcomes and potential targets for treatment of patients with HP-induced GC.

Highlights

Gastric cancer (GC) is the fifth most common and fourth most common cause of cancer-related death worldwide (Sung et al, 2021)
To identify metabolism-related genes (MRGs) that play an important role in the development of Helicobacter pylori (HP)-induced GC, we first extracted the major metabolic pathway genes in gene set enrichment analysis (GSEA) using the TCGA and GEO databases to identify the intersections (Figure 1A)
The black module was found to have the highest correlation with HP infection (Figure 1B), and these module genes (HP-MRGs, Supplementary Table S1) were selected for further analysis

Summary

Introduction

Gastric cancer (GC) is the fifth most common and fourth most common cause of cancer-related death worldwide (Sung et al, 2021). Chronic Helicobacter pylori (HP) infection is considered the major cause of non-cardia gastric cancer, with almost all cases due to the presence of these bacteria (Plummer et al, 2015). Despite the high significance of HP for human health, it seems that the molecular infection mechanisms and intracellular signaling pathways during colonization have not been fully elucidated. The identification of new subtypes and functional pathways of HP-induced GC by recognizable molecular profiles and the exploration of novel key gene targets for monitoring GC progression are urgent requirements. Changes in the expression of metabolism-related genes may underlie the molecular mechanism of cancer cell metabolic reprogramming. Chronic Helicobacter pylori (HP) infection is considered the major cause of non-cardia gastric cancer (GC). How HP infection influences the metabolism and further regulates the progression of GC remains unknown

Methods

Results

Conclusion