{"title":"NFAT2通过作为TGF-β1/SMAD信号通路的转录共激活因子，诱导肝癌上皮-间质转化，诱导肿瘤细胞增殖和转移。","authors":"Yuqi Liu, Wenhui Mo, Weijie Sun, Jianqing Chen, Jiaojiao Chen, Yueyue Li, Dengyu Han, Weiqi Dai, Ruling Zhang","doi":"10.1007/s10620-025-08890-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The role of NFAT2 in liver cancer is conflicting, with evidence suggesting both oncogenic and tumor-suppressive effects. A clear understanding of its expression, function, regulation, and mechanism of action in liver cancer remains critical.</p><p><strong>Objectives: </strong>To examine the expression levels, biological functions, regulatory mechanisms, and downstream pathways of NFAT2 in liver cancer and its metastasis.</p><p><strong>Methods: </strong>The expression of NFAT2 was analyzed in liver cancer patients and correlated with clinical outcomes. Functional assays, including proliferation, migration, invasion, and xenograft models, were employed to assess the effects of NFAT2 upregulation and downregulation. Molecular analyses were conducted to identify key pathways and protein interactions underpinning NFAT2's effects. The therapeutic potential of NFAT2 inhibition in combination with sorafenib was also evaluated.</p><p><strong>Results: </strong>NFAT2 overexpression was associated with poor prognosis and shorter disease-free survival in liver cancer patients. Upregulation of NFAT2 promoted hepatoma cell proliferation, migration, and invasion, while its downregulation impaired these pro-oncogenic effects. Mechanistically, NFAT2 enhanced the epithelial-to-mesenchymal transition (EMT) by increasing mesenchymal marker expression (N-cadherin, vimentin, MMP9) and decreasing invasion inhibitors (E-cadherin, ZO-1). It physically interacted with SMAD3 and p300, thereby activating the TGF-β1/SMAD pathway to drive tumor progression. NFAT2 knockdown or inhibition re-sensitized tumor cells to sorafenib, indicating its promising therapeutic potential.</p><p><strong>Conclusion: </strong>NFAT2 acts as a transcriptional co-activator of the TGF-β1/SMAD signaling pathway, promoting liver cancer progression and metastasis. Its inhibition could serve as a novel therapeutic strategy for the treatment of advanced liver cancer, particularly in combination with sorafenib.</p>","PeriodicalId":11378,"journal":{"name":"Digestive Diseases and Sciences","volume":" ","pages":"1799-1812"},"PeriodicalIF":2.5000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NFAT2 Induces Tumor Cell Proliferation and Metastasis by Acting as a Transcriptional Co-activator of the TGF-β1/SMAD Signaling Pathway and Inducing the Epithelial-Mesenchymal Transition in Liver Cancer.\",\"authors\":\"Yuqi Liu, Wenhui Mo, Weijie Sun, Jianqing Chen, Jiaojiao Chen, Yueyue Li, Dengyu Han, Weiqi Dai, Ruling Zhang\",\"doi\":\"10.1007/s10620-025-08890-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The role of NFAT2 in liver cancer is conflicting, with evidence suggesting both oncogenic and tumor-suppressive effects. A clear understanding of its expression, function, regulation, and mechanism of action in liver cancer remains critical.</p><p><strong>Objectives: </strong>To examine the expression levels, biological functions, regulatory mechanisms, and downstream pathways of NFAT2 in liver cancer and its metastasis.</p><p><strong>Methods: </strong>The expression of NFAT2 was analyzed in liver cancer patients and correlated with clinical outcomes. Functional assays, including proliferation, migration, invasion, and xenograft models, were employed to assess the effects of NFAT2 upregulation and downregulation. Molecular analyses were conducted to identify key pathways and protein interactions underpinning NFAT2's effects. The therapeutic potential of NFAT2 inhibition in combination with sorafenib was also evaluated.</p><p><strong>Results: </strong>NFAT2 overexpression was associated with poor prognosis and shorter disease-free survival in liver cancer patients. Upregulation of NFAT2 promoted hepatoma cell proliferation, migration, and invasion, while its downregulation impaired these pro-oncogenic effects. Mechanistically, NFAT2 enhanced the epithelial-to-mesenchymal transition (EMT) by increasing mesenchymal marker expression (N-cadherin, vimentin, MMP9) and decreasing invasion inhibitors (E-cadherin, ZO-1). It physically interacted with SMAD3 and p300, thereby activating the TGF-β1/SMAD pathway to drive tumor progression. NFAT2 knockdown or inhibition re-sensitized tumor cells to sorafenib, indicating its promising therapeutic potential.</p><p><strong>Conclusion: </strong>NFAT2 acts as a transcriptional co-activator of the TGF-β1/SMAD signaling pathway, promoting liver cancer progression and metastasis. Its inhibition could serve as a novel therapeutic strategy for the treatment of advanced liver cancer, particularly in combination with sorafenib.</p>\",\"PeriodicalId\":11378,\"journal\":{\"name\":\"Digestive Diseases and Sciences\",\"volume\":\" \",\"pages\":\"1799-1812\"},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Digestive Diseases and Sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s10620-025-08890-7\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/3/4 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Digestive Diseases and Sciences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10620-025-08890-7","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/4 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
NFAT2 Induces Tumor Cell Proliferation and Metastasis by Acting as a Transcriptional Co-activator of the TGF-β1/SMAD Signaling Pathway and Inducing the Epithelial-Mesenchymal Transition in Liver Cancer.
Background: The role of NFAT2 in liver cancer is conflicting, with evidence suggesting both oncogenic and tumor-suppressive effects. A clear understanding of its expression, function, regulation, and mechanism of action in liver cancer remains critical.
Objectives: To examine the expression levels, biological functions, regulatory mechanisms, and downstream pathways of NFAT2 in liver cancer and its metastasis.
Methods: The expression of NFAT2 was analyzed in liver cancer patients and correlated with clinical outcomes. Functional assays, including proliferation, migration, invasion, and xenograft models, were employed to assess the effects of NFAT2 upregulation and downregulation. Molecular analyses were conducted to identify key pathways and protein interactions underpinning NFAT2's effects. The therapeutic potential of NFAT2 inhibition in combination with sorafenib was also evaluated.
Results: NFAT2 overexpression was associated with poor prognosis and shorter disease-free survival in liver cancer patients. Upregulation of NFAT2 promoted hepatoma cell proliferation, migration, and invasion, while its downregulation impaired these pro-oncogenic effects. Mechanistically, NFAT2 enhanced the epithelial-to-mesenchymal transition (EMT) by increasing mesenchymal marker expression (N-cadherin, vimentin, MMP9) and decreasing invasion inhibitors (E-cadherin, ZO-1). It physically interacted with SMAD3 and p300, thereby activating the TGF-β1/SMAD pathway to drive tumor progression. NFAT2 knockdown or inhibition re-sensitized tumor cells to sorafenib, indicating its promising therapeutic potential.
Conclusion: NFAT2 acts as a transcriptional co-activator of the TGF-β1/SMAD signaling pathway, promoting liver cancer progression and metastasis. Its inhibition could serve as a novel therapeutic strategy for the treatment of advanced liver cancer, particularly in combination with sorafenib.
期刊介绍：
Digestive Diseases and Sciences publishes high-quality, peer-reviewed, original papers addressing aspects of basic/translational and clinical research in gastroenterology, hepatology, and related fields. This well-illustrated journal features comprehensive coverage of basic pathophysiology, new technological advances, and clinical breakthroughs; insights from prominent academicians and practitioners concerning new scientific developments and practical medical issues; and discussions focusing on the latest changes in local and worldwide social, economic, and governmental policies that affect the delivery of care within the disciplines of gastroenterology and hepatology.
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