Jiang Jiang, Li Jianfang, Yao Weiwu, Wang Wenfang, Shi Bowen, Yuan Fei, Dong Jingyan, Zhang Huan
Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Cell Dev Biol. 2021 Apr 27;9:662624. doi: 10.3389/fcell.2021.662624. eCollection 2021.
Gastric cancer (GC), characterized by uncontrolled growth, is a common malignant tumor of the digestive system. The Wnt signaling pathway plays an important role in the tumorigenesis and proliferation of GC. Many studies on this signaling pathway have focused on its intracellular regulatory mechanism, whereas little attention has been given to extracellular regulatory factors. Dickkopf-1 (Dkk1) is a secretory glycoprotein, and it can bind inhibit activation of the Wnt pathway. However, the regulation and mechanism of DKK1 in the proliferation of GC remain unclear. FOXC1 plays an important role in organ development and tumor growth, but its role in GC tumor growth remains unknown. In this study, we found that the FOXC1 is highly expressed in patients with GC and high expression of FOXC1 correlates to poor prognosis. In addition, we found that the Wnt signaling pathway in GC cells with high FOXC1 expression was strongly activated. FOXC1 negatively regulates DKK1 expression by binding to its promoter region, thereby promoting the activation of Wnt pathway. FOXC1 can also form a complex with unphosphorylated β-catenin protein in the cytoplasm and then dissociates from β-catenin in the nucleus, thereby promoting the entry of β-catenin into the nucleus and regulating expression of c-MYC, which promotes the proliferation of GC cells. Our study not only reveals the function and mechanism of FOXC1 in GC, but also provides a potential target for clinic GC treatment.
胃癌（GC）以不受控制的生长为特征，是消化系统常见的恶性肿瘤。Wnt信号通路在GC的肿瘤发生和增殖中起重要作用。许多关于该信号通路的研究都集中在其细胞内调节机制上，而对细胞外调节因子关注较少。Dickkopf-1（Dkk1）是一种分泌性糖蛋白，它可以结合并抑制Wnt通路的激活。然而，DKK1在GC增殖中的调节作用和机制仍不清楚。FOXC1在器官发育和肿瘤生长中起重要作用，但其在GC肿瘤生长中的作用尚不清楚。在本研究中，我们发现FOXC1在GC患者中高表达，且FOXC1的高表达与不良预后相关。此外，我们发现FOXC1高表达的GC细胞中的Wnt信号通路被强烈激活。FOXC1通过与DKK1的启动子区域结合来负向调节DKK1的表达，从而促进Wnt通路的激活。FOXC1还可以在细胞质中与未磷酸化的β-连环蛋白形成复合物，然后在细胞核中与β-连环蛋白解离，从而促进β-连环蛋白进入细胞核并调节c-MYC的表达，进而促进GC细胞的增殖。我们的研究不仅揭示了FOXC1在GC中的功能和机制，还为临床GC治疗提供了一个潜在靶点。
