Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
Cancer Res. 2024 Nov 4;84(21):3574-3588. doi: 10.1158/0008-5472.CAN-23-3074.
The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer. As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. In this study, we identified a vital role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired gastric cancer spheroid formation and reduced stemness marker expression, whereas FOXP4 upregulation potentiated cancer cell stemness. RNA sequencing analysis revealed SOX12 as a downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small-molecule screen identified 42-(2-tetrazolyl) rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed gastric cancer tumor growth and enhanced the efficacy of 5-fluorouracil chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in gastric cancer regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for gastric cancer. Significance: Hippo-YAP1 signaling maintains stemness in gastric cancer by upregulating FOXP4, identifying FOXP4 as a stemness biomarker and therapeutic target that could help improve patient outcomes.
Hippo-YAP1 通路是一个进化上保守的信号级联，它控制着器官的大小和组织的再生。Hippo-YAP1 信号的失调促进了几种类型的癌症的发生和发展，包括胃癌。由于 Hippo-YAP1 通路调节着数千个基因的表达，因此确定哪些靶基因有助于由 YAP1 驱动的致癌程序对于确定规避策略非常重要。在这项研究中，我们通过维持干细胞特性和促进腹膜转移，确定了叉头框蛋白 4（FOXP4）在 YAP1 驱动的胃癌发生中的重要作用。FOXP4 的缺失会损害胃癌球体的形成并降低干细胞标志物的表达，而 FOXP4 的上调则增强了癌细胞的干性。RNA 测序分析揭示了 SOX12 是 FOXP4 的下游靶标，功能研究证实 SOX12 支持 YAP1 诱导的致癌作用中的干细胞特性。小分子筛选鉴定出 42-(2-四唑基)雷帕霉素是 FOXP4 的抑制剂，靶向 FOXP4 可抑制胃癌肿瘤生长，并增强体内 5-氟尿嘧啶化疗的疗效。综上所述，这些发现表明，YAP1 在胃癌中上调 FOXP4 通过上调 SOX12 来调节干细胞特性和肿瘤发生。靶向 YAP1-FOXP4-SOX12 轴可能是治疗胃癌的一种潜在策略。意义：Hippo-YAP1 信号通过上调 FOXP4 来维持胃癌中的干细胞特性，确定 FOXP4 为干细胞标志物和治疗靶点，这可能有助于改善患者的预后。
