FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway.
FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway.
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FOXC1通过激活Wnt信号通路负调控DKK1表达促进胃癌细胞增殖
DOI：
10.3389/fcell.2021.662624
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发表时间：
2021
影响因子：
5.5
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Jiang J;Li J;Yao W;Wang W;Shi B;Yuan F;Dong J;Zhang H
胃癌（Gastric cancer，GC）是一种常见的消化系统恶性肿瘤，以生长失控为特征. Wnt信号通路在胃癌的发生和增殖中起重要作用。目前对该信号通路的研究主要集中在其胞内调控机制上，而对胞外调控因子的研究较少。Dickkopf-1（Dkk 1）是一种分泌型糖蛋白，能抑制Wnt信号通路的激活。然而，DKK 1在胃癌细胞增殖中的调控及机制尚不清楚。FOXC 1在器官发育和肿瘤生长中起重要作用，但其在GC肿瘤生长中的作用仍不清楚。在这项研究中，我们发现FOXC 1在胃癌患者中高表达，FOXC 1的高表达与预后不良相关。此外，我们发现在FOXC 1高表达的GC细胞中Wnt信号通路被强烈激活。FOXC 1通过与DKK 1的启动子区结合负调控DKK 1的表达，从而促进Wnt通路的激活。FOXC 1还可以与胞浆中未磷酸化的β-catenin蛋白形成复合物，然后在细胞核中与β-catenin解离，从而促进β-catenin进入细胞核，调节c-MYC的表达，从而促进GC细胞的增殖。本研究不仅揭示了FOXC 1在胃癌中的作用和机制，而且为临床治疗胃癌提供了一个潜在的靶点。
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.
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影响因子：
64.8
作者：
Sansom, Owen J.;Meniel, Valerie S.;Clarke, Alan R.
通讯作者：
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DOI：
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