Abstract
Gastric cancer (GC) is among the most treatment-refractory epithelial malignancies. Aberrant activation of Wnt/β-catenin-signaling has been implicated in a variety of human cancers, including gastric cancer. Here we report that the elevated expression of lymphoid enhancer binding factor 1 (Lef1) is associated with the TNM (tumor– node–metastasis) stage of gastric cancer. Subsequently, 2,4-diamino-quinazoline (2,4-DAQ), a selective inhibitor of Lef1, was identified to suppress the expression of Wnt/β-catenin target genes such as AXIN2, MYC and LGR5 and result in the suppression of gastric cancer cell growth through the apoptotic pathway. The 2,4-DAQ also exhibited an inhibitory effect on the migration/invasion of gastric cancer cells. Importantly, the treatment of human gastric tumor xenograft with 2,4-DAQ suppressed tumor growth in a nude mouse model. Furthermore, 2,4-DAQ appears effective on patient-derived organoids (PDOs). Transcriptome sequencing analysis also revealed that 2,4-DAQ are more effective on the gastric cancers that exhibit higher expression levels of Wnt-signaling pathway-related genes than their adjacent normal gastric tissues.
Highlights
Gastric cancer (GC) is one of the most common cancers and the 2nd cause of cancer-related deaths worldwide [1]
Through RNA sequencing and TruSeq targeted RNA Wnt-signaling panel analysis, we found that the lymphoid enhancer binding factor 1 (Lef1) gene was significantly upregulated in GC tissues and the expression level of Lef1 was positively correlated with the cancer stage
To avoid the interference of the low-quality RNAs that were prepared from the formalin-fixed samples, we utilized the preassembled gene panels (Wnt pathways panels) for targeted RNA sequencing to analyze the expression levels of Wnt signaling-related genes in GC
Summary
Gastric cancer (GC) is one of the most common cancers and the 2nd cause of cancer-related deaths worldwide [1]. Recent large-scale studies in molecular subtyping further defined GC into four subtypes, including Epstein–Barr virus-positive tumors, microsatellite unstable tumors, genomically stable tumors and tumors with chromosomal instability across genomic, transcriptomic and proteomic levels [9]. These classifications provide a roadmap for patient stratification, they have no impact on the choice of systemic treatment at present. Through RNA sequencing and TruSeq targeted RNA Wnt-signaling panel analysis, we found that the Lef gene was significantly upregulated in GC tissues and the expression level of Lef was positively correlated with the cancer stage.
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