image: (A) Unsupervised clustering of 186 glycogenes in the TCGA-STAD cohort (n = 412) separated GC patients into two clusters (A and B) and four subclusters (A1, A2, B1, and B2). The annotations by the Lauren classification (Intestinal, Diffuse, Mixed, and NA; n = 274), the TCGA (Nature 2014) classification (EBV, CIN, MSI, and GS; n = 274), and patients' age were respectively indicated for the same GC patient. The 138 new GC cases without Lauren or TCGA classification information were defined as “new case” (in yellow). The black arrowhead indicates GXYLT2. (B, C) Kaplan–Meier plots for overall survival (B) and disease-free survival (C) in GC patients at stages I-III from the TCGA-STAD dataset, comparing that in subcluster B2 with the other three subclusters (A1, A2, and B1). (D) Clustering based on 12-glycogene signature in GC patients from the TCGA-STAD cohort (n = 412). Two clusters (I and II) were compared with the Lauren classification, the TCGA (Nature 2014) classification, and patients' age. (E) Kaplan–Meier plot for overall survival in GC patients from the TCGA-STAD dataset, stratified by 12-glycogene signature classification as cluster I and cluster II. (F) Pearson correlation coefficients (r) for the correlations between the expression levels of the 12 glycogenes and molecular features, including G-DIF, G-INT, EMT-up, and EMT-down, across seven independent cohorts (n = 1547 total). The heatmap was composed of color-coded blocks: red, r > 0.25, p < 0.05; blue, r < −0.25, p < 0.05; white, |r| ≤ 0.25, p < 0.05; gray, p ≥ 0.05. p values were calculated with the χ2 test (A and D). GC, gastric cancer; TCGA-STAD, TCGA (stomach cancer); G-INT, genomic intestinal; G-DIF, genomic diffuse; EMT, epithelial–mesenchymal transition. EBV, Epstein–Barr virus; MSI, microsatellite instability; CIN, chromosomal instability; GS, genetically stable; EMT-up, up-regulated EMT; EMT-down, down-regulated EMT; GXYLT2, glucoside xylosyltransferase 2.
Credit: Jiale Yang, Jiajun Wu, Ziqiang Chen, Xiangyun Hou, Xiaojing Li, Zhaorui Liu, Kai Yin, Tao Pang, Ruimin Huang, Jun Yan
This new study published in Genes & Diseases by researchers from Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Fudan University and The First Affiliated Hospital of Naval Medical University identifies glucoside xylosyltransferase 2 (GXYLT2) as a key prognostic biomarker and functional regulator of tumor aggressiveness in gastric cancer.
By integrating transcriptomic and clinical data from seven independent cohorts encompassing more than 1,500 patients, the researchers established a glycosylation-related molecular classification that robustly correlated with tumor stage, recurrence, and patient survival. Within this signature, GXYLT2 emerged as the most strongly prognostic gene.
Clinical analyses revealed that elevated GXYLT2 expression is significantly associated with advanced disease stage, poor overall survival, and reduced disease-free survival. Notably, GXYLT2 levels were markedly higher in the diffuse subtype of gastric cancer compared with the intestinal subtype, highlighting its subtype-specific relevance. Immunohistochemical validation further confirmed strong GXYLT2 expression in diffuse-type tumor tissues, supporting its translational potential as a prognostic marker.
Functional studies demonstrated that GXYLT2 is not merely correlative but actively promotes malignant phenotypes. Genetic depletion of GXYLT2 significantly suppressed proliferation, invasion, and sphere-forming capacity in diffuse-type gastric cancer cells, while exerting minimal effects in intestinal-type cells. Conversely, ectopic expression of GXYLT2 alone was insufficient to confer aggressiveness in intestinal-type models, indicating that GXYLT2 operates within a context-dependent oncogenic network.
Mechanistically, the researchers reveal that GXYLT2 drives tumor progression through activation of the Wnt/β-catenin signaling pathway. Loss of GXYLT2 increased β-catenin phosphorylation, reduced nuclear accumulation, and diminished transcription of downstream Wnt target genes. Further investigation identified protein phosphatase 2A (PP2A) as a critical intermediary, showing that GXYLT2 suppresses PP2A activity, thereby sustaining β-catenin signaling. Restoration of PP2A function following GXYLT2 knockdown effectively attenuated Wnt-driven oncogenic signaling.
In vivo experiments corroborated these findings, demonstrating that GXYLT2 silencing significantly inhibited tumor growth and proliferation in xenograft models.
Together, these results establish GXYLT2 as both a clinically relevant prognostic biomarker and a mechanistic driver of Wnt/β-catenin–dependent aggressiveness in diffuse-type gastric cancer. Targeting GXYLT2 or its downstream signaling axis may provide a novel strategy for improving molecular stratification and therapeutic intervention in gastric cancer.
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