What question did this study set out to answer?

The aim was to investigate the role of TRIM26 deficiency in lymph node metastasis and gemcitabine response in gastric cancer.

February 8, 2026Open Access

TRIM26 deficiency drives gastric cancer lymph node metastasis via TGF-β signaling activation and modulates gemcitabine response

Key Points

The aim was to investigate the role of TRIM26 deficiency in lymph node metastasis and gemcitabine response in gastric cancer.
Integrated single-cell and bulk transcriptomic data from GEO and TCGA.
Constructed co-expression networks with hdWGCNA, followed by core gene screening via machine learning algorithms.
Performed pseudotime trajectory analysis to trace cell state transitions and analyzed cell communication and metabolic pathways.
Utilized computational pharmacology for drug sensitivity prediction and validated findings experimentally.
TRIM26 downregulation correlated with lymph node metastasis and poor patient survival.
Loss of TRIM26 in epithelial cells activated TGF-β signaling and promoted pro-metastatic interactions with immune cells.
TRIM26-low tumors exhibited greater resistance to gemcitabine, indicated by higher estimated IC 50 values.
TRIM26 overexpression reduced tumor growth and invasiveness when treated with gemcitabine.

Abstract

Background Globally, gastric cancer (GC) is a predominant cause of cancer-related death. Lymph node metastasis (LNM) and chemoresistance constitute two major barriers to improving outcomes, as LNM signifies advanced disease and chemoresistance consequently leads to treatment failure. This study systematically investigates the key molecular drivers underlying LNM and chemoresistance in GC to assess their therapeutic relevance. Methods Our study integrated single-cell and bulk transcriptomic data from GEO and TCGA. The analytical workflow comprised: Firstly, hdWGCNA for co-expression network construction; Secondly, a combination of machine learning algorithms (LASSO, random forest, and SVM-RFE) for core gene screening; Thirdly, pseudotime trajectory analysis (Monocle2/3) to delineate cell state transitions. Cell-cell communication and metabolic pathways were profiled using CellChat and scMetabolism, respectively. Computational pharmacology involved drug sensitivity prediction with the pRRophetic algorithm, complemented by molecular docking and dynamics simulations for structural insights. Finally, TRIM26’s functional roles were experimentally validated through CCK-8, Transwell, and colony formation assays, alongside protein-level verification by immunohistochemistry. Results Downregulation of TRIM26 in GC correlated strongly with LNM and poor survival. At single-cell resolution, TRIM26 loss in epithelial cells fueled pro-metastatic crosstalk with endothelial cells and macrophages through SELE-CD44 and SPP1-CD44/integrin axes. This triggered TGF-β activation, TP53 network dysregulation, and metabolic reprogramming of taurine and pantothenate/CoA pathways. TRIM26-low tumors were predicted to be less sensitive to gemcitabine, consistent with higher estimated IC 50 values, a premise bolstered by computational evidence of stable, direct drug binding (free energies: −6.7 and −5.5 kcal/mol) and sustained interactions in 100 ns simulations. Critically, TRIM26 overexpression curtailed tumor growth and invasiveness in the presence of gemcitabine. Conclusion TRIM26 inhibits LNM by modulating TGF-β signaling and remodeling the tumor microenvironment. Clinically, low TRIM26 expression identifies tumors with reduced sensitivity to gemcitabine, reflected by higher estimated IC 50 values—a correlation underpinned by computational models demonstrating stable drug binding. Thus, TRIM26 serves as a integrated prognostic and predictive biomarker, positioning it as a promising theranostic target to inform precision therapy strategies in GC.

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