A novel Wnt/β-catenin signaling gene signature for progression and metastasis of gastric cancer.

[BACKGROUNDS] As cancer progresses through various stages of malignancy, metastasis, and drug resistance, the Wnt/-catenin signaling is frequently dysregulated. Despite advancements in medical technology and therapeutic strategies, the prognosis for numerous gastric cancer patients remains unfavorable.

[METHODS] For the analysis of prognostic signature genes associated with Wnt signaling in GC, we used LASSO (least absolute shrinkage and selection operator) regression. To explore the function, cell specificity, and transcriptional regulation of the signature gene Carboxypeptidase Z (CPZ), we conducted co-expression analysis, single-cell RNA sequencing data analysis, transcription factor prediction, and dual luciferase reporter assay. The knockdown and overexpression experiments were also performed to observe the changes in the downstream gene expression, as well as the influence on the biological functions of GC cells.

[RESULTS] We identified a five-gene signature, including CPZ, Collagen Triple Helix Repeat Containing-1 (CTHRC1), Dickkopf-1 (DKK1), Epidermal Growth Factor (EGF), and Glypican Proteoglycan-3 (GPC3), with risk scores predictive of the prognosis of GC patients. We found that the adipocyte enhancer binding protein 1 (AEBP1) and transcription factor 3 (TCF3) could interact in the nucleus and synergistically enhance the expression of Wnt signaling-associated genes, including WNT2/FZD2 (Wnt family member 2/frizzled class receptor 2) and VIM (vimentin), thus promoting the invasion, migration, and malignant metastasis of GC.

[CONCLUSIONS] Our study offers a precise gene-signature prediction method for the prognosis of GC. We discovered the synergistic effect of AEBP1 and TCF3 in the nucleus on GC metastasis. GC may benefit from the identification of this potential therapeutic target.