Diana Lashidua Fernandez Coto (Cuernavaca / MX), Jeovanis Gil Valdés (Lund / SE), Sergio Manuel Encarnación-Guevara (Cuernavaca / MX), Guadalupe Ayala Aguilar (Morelos / MX), György Marko-Varga (Lund / SE), Roberto Herrera Goepfert (Mexico City / MX)
Introduction
Gastric cancer remains a significant public health challenge, ranking as the fourth leading cause of cancer-related mortality and the fifth leading cause of cancer incidence worldwide. Patients with diffuse-type gastric cancer (DGC) face a particularly poor prognosis compared to those with intestinal-type gastric cancer (IGC), which benefits from well-defined preneoplastic lesions. The lack of identifiable preneoplastic markers for DGC hinders effective surveillance and prevention. Thus, identifying molecular biomarkers that contribute to the risk of developing DGC is crucial for informing novel preventive strategies.
Methods
Fresh frozen biopsies of lesions and adjacent tissues were collected from 42 patients diagnosed with chronic gastritis (CG), diffuse-type gastric cancer (DGC), or intestinal-type gastric cancer (IGC). These 84 samples, consisting of pairs from 15 DGC, 9 IGC, and 18 CG patients, were analyzed using quantitative proteomics. High-resolution variable window Data Independent Acquisition Mass Spectrometry (DIA-MS) was performed via LC-MS/MS. Peptide and protein identification was conducted using DIA-NN. Data processing and statistical analyses were carried out with Perseus v2.0.10.0, R, and GraphPad Prism. Additionally, pathway and biological processes enrichment analyses were performed in R and the Gene Set Enrichment Analysis program (GSEA).
Results
Proteomic analysis identified and quantified 9,040 proteins. IGC exhibited relatively higher expression of immune response proteins, including those involved in the interferon response, as well as spliceosome proteins, compared to DGC. Conversely, DGC showed elevated expression of mitochondrial process proteins, particularly subunits of complex I of the electron transport chain, and proteins involved in the Krebs cycle and oxidative phosphorylation. Notably, there was an inverse correlation between the expression of mitochondrial pathways and immune response proteins. Differential analysis between cancerous and adjacent tissues revealed a decrease in mitochondrial processes in both DGC and IGC, with the loss of mitochondrial function being more pronounced in IGC.
Conclusions
Our comprehensive proteomic profiling of DGC and IGC, compared with chronic gastritis, provides detailed molecular insights into the distinct and shared pathways underlying these gastric cancer types. The identification of an inverse correlation between mitochondrial pathway activity and immune response proteins highlights key differences in the tumor microenvironment of DGC and IGC. These findings significantly enhance our understanding of gastric cancer etiology and may inform the development of more effective, targeted therapeutic strategies. Furthermore, the distinct molecular signatures identified in this study could serve as potential biomarkers for early detection and personalized treatment of gastric cancer.