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 tumour 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 tumour 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 tumour 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 tumour progression through activation of the Wnt/β-catenin signalling 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 signalling.

Restoration of PP2A function following GXYLT2 knockdown effectively attenuated Wnt-driven oncogenic signalling.

In vivo experiments corroborated these findings, demonstrating that GXYLT2 silencing significantly inhibited tumour 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 signalling axis may provide a novel strategy for improving molecular stratification and therapeutic intervention in gastric cancer.

Source: Compuscript Ltd