FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway
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 mechanis...
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.662624/full |
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| author | Jiang Jiang Jianfang Li Weiwu Yao Wenfang Wang Bowen Shi Fei Yuan Jingyan Dong Huan Zhang |
| author_facet | Jiang Jiang Jianfang Li Weiwu Yao Wenfang Wang Bowen Shi Fei Yuan Jingyan Dong Huan Zhang |
| author_sort | Jiang Jiang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T23:04:50Z |
| format | Article |
| id | doaj.art-3609924f866d426d8c1be5187b63f6f2 |
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| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-16T23:04:50Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-3609924f866d426d8c1be5187b63f6f22022-12-21T22:12:36ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-04-01910.3389/fcell.2021.662624662624FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling PathwayJiang Jiang0Jianfang Li1Weiwu Yao2Wenfang Wang3Bowen Shi4Fei Yuan5Jingyan Dong6Huan Zhang7Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Radiology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Ocular Fundus Diseases, Shanxi Eye Hospital, Shanxi, ChinaDepartment of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaGastric 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.662624/fullgastric cancerFOXC1DKK1c-MYCproliferation |
| spellingShingle | Jiang Jiang Jianfang Li Weiwu Yao Wenfang Wang Bowen Shi Fei Yuan Jingyan Dong Huan Zhang FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway Frontiers in Cell and Developmental Biology gastric cancer FOXC1 DKK1 c-MYC proliferation |
| title | FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway |
| title_full | FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway |
| title_fullStr | FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway |
| title_full_unstemmed | FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway |
| title_short | FOXC1 Negatively Regulates DKK1 Expression to Promote Gastric Cancer Cell Proliferation Through Activation of Wnt Signaling Pathway |
| title_sort | foxc1 negatively regulates dkk1 expression to promote gastric cancer cell proliferation through activation of wnt signaling pathway |
| topic | gastric cancer FOXC1 DKK1 c-MYC proliferation |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.662624/full |
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