2. Academic Validation
  3. 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

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

  • Dig Dis Sci. 2025 Mar 4. doi: 10.1007/s10620-025-08890-7.
Yuqi Liu # 1,  Wenhui Mo # 2,  Weijie Sun # 3,  Jianqing Chen 2,  Jiaojiao Chen 2,  Yueyue Li 2,  Dengyu Han 1,  Weiqi Dai # 2,  Ruling Zhang # 4
Affiliations

Affiliations

  • 1 School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People's Republic of China.
  • 2 Department of Gastroenterology, Shidong Hospital, Shidong Hospital Affiliated to University of Shanghai for Science and Technology, No. 999, Shiguang Road, Yangpu District, Shanghai, People's Republic of China.
  • 3 Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, People's Republic of China.
  • 4 Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, No. 274, Zhijiangzhong Road, Jingan District, Shanghai, People's Republic of China. zhangruling_mtw@aliyun.com.
  • # Contributed equally.
PMID: 40038210 DOI: 10.1007/s10620-025-08890-7
Abstract

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.

Keywords

Epithelial–mesenchymal transition; Liver cancer; NFAT2; SMAD3; p300.

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