Chang Zhengyao, Gao Yunhe, Chen Peng, Gao Wenxing, Zhao Wen, Wu Di, Liang Wenquan, Chen Zhida, Chen Lin, Xi Hongqing
Medical School of Chinese PLA Beijing 100853, China.
Department of General Surgery, The First Medical Center of Chinese PLA General Hospital Beijing 100853, China.
Am J Cancer Res. 2024 Jul 15;14(7):3433-3450. doi: 10.62347/UXWK4038. eCollection 2024.
Thrombospondin-2 (THBS2), a secreted extracellular matrix protein, plays a crucial role in various biological processes including angiogenesis, tissue remodeling, and inflammation. Our study focuses on its function in human gastric cancer (GC). Through bioinformatics and tumor tissue analysis, we compared THBS2 expression in GC tissues and adjacent tissues, and predicted regulatory upstream and downstream molecules. The direct regulatory effect of miR-29b-3p on THBS2 was evaluated through dual-luciferase reporter assays, showing that miR-29b-3p targets the 3'-UTR of THBS2 mRNA, reducing its expression in GC cells. The influence of THBS2 on tumorigenesis and stemness was examined on protein expression levels via Western blot. In vivo, THBS2's role was investigated through xenograft and metastasis assays in nude mice, demonstrating that downregulation of THBS2 impairs GC tumorigenesis and liver metastasis. Our study identified THBS2 as a highly expressed prognostic factor in GC patients. Functionally, THBS2 promotes GC progression through the Notch signaling pathway by regulating Notch3, NEY1, and HES1 proteins, and sustains cancer stem cell-like characteristics by Notch3, including the expression of CD44, Nanog, OCT4, and SOX2. In sum, our study reveals that THBS2 promotes GC progression and stemness, modulated negatively by miR-29b-3p. This suggests potential therapeutic targets within the THBS2/Notch signaling axis for combating gastric cancer.
血小板反应蛋白-2（THBS2）是一种分泌型细胞外基质蛋白，在包括血管生成、组织重塑和炎症在内的各种生物学过程中发挥关键作用。我们的研究聚焦于其在人类胃癌（GC）中的功能。通过生物信息学和肿瘤组织分析，我们比较了GC组织和邻近组织中THBS2的表达，并预测了其上下游调控分子。通过双荧光素酶报告基因实验评估了miR-29b-3p对THBS2的直接调控作用，结果表明miR-29b-3p靶向THBS2 mRNA的3'-UTR，降低其在GC细胞中的表达。通过蛋白质印迹法在蛋白质表达水平上检测了THBS2对肿瘤发生和干性的影响。在体内，通过裸鼠异种移植和转移实验研究了THBS2的作用，结果表明THBS2的下调会损害GC的肿瘤发生和肝转移。我们的研究确定THBS2是GC患者中高表达的预后因素。在功能上，THBS2通过调节Notch3、NEY1和HES1蛋白，经Notch信号通路促进GC进展，并通过Notch3维持癌症干细胞样特征，包括CD44、Nanog、OCT4和SOX2的表达。总之，我们的研究表明THBS2促进GC进展和干性，而miR-29b-3p对其起负向调节作用。这提示THBS2/Notch信号轴可能是对抗胃癌的潜在治疗靶点。
