Chen Jia, Jiang Fei, Niu Kaiyi, Zhao Haodong, Li L I, Yu Hongzhu
Department of General Surgery, Fuyang Hospital Affiliated of Anhui Medical University, Fuyang, 236000, China.
Department of Emergency Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China.
Oncol Res. 2025 Apr 18;33(5):1199-1215. doi: 10.32604/or.2024.054366. eCollection 2025.
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.
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.
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.
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.
随着癌症经历恶性、转移和耐药的各个阶段进展，Wnt/β-连环蛋白信号通路经常失调。尽管医疗技术和治疗策略取得了进展，但许多胃癌患者的预后仍然不佳。
为了分析与胃癌中Wnt信号相关的预后特征基因，我们使用了套索（最小绝对收缩和选择算子）回归。为了探究特征基因羧肽酶Z（CPZ）的功能、细胞特异性和转录调控，我们进行了共表达分析、单细胞RNA测序数据分析、转录因子预测和双荧光素酶报告基因检测。还进行了敲低和过表达实验，以观察下游基因表达的变化，以及对胃癌细胞生物学功能的影响。
我们鉴定出一个包含CPZ、含胶原蛋白三螺旋重复序列-1（CTHRC1）、Dickkopf-1（DKK1）、表皮生长因子（EGF）和磷脂酰肌醇蛋白聚糖-3（GPC3）的五基因特征，其风险评分可预测胃癌患者的预后。我们发现脂肪细胞增强子结合蛋白1（AEBP1）和转录因子3（TCF3）可在细胞核内相互作用，并协同增强包括WNT2/FZD2（Wnt家族成员2/卷曲蛋白家族受体2）和波形蛋白（VIM）在内的Wnt信号相关基因的表达，从而促进胃癌的侵袭、迁移和恶性转移。
我们的研究为胃癌预后提供了一种精确的基因特征预测方法。我们发现AEBP1和TCF3在细胞核内对胃癌转移具有协同作用。识别这一潜在治疗靶点可能使胃癌患者受益。
