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FOXD3 regulates anaplastic thyroid cancer progression
Huabin Yin1, Tong Meng1, Lei Zhou2
1Department of Orthopedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, PR China.
Abstract:
Anaplastic thyroid cancer (ATC) is an aggressive malignancy with poor prognosis. It was reported that Forkhead box D3 (FOXD3) transcription factor is associated with several cancers. We investigated its antitumorigenic role of ATC in this study. The ATC cell lines SW1736 and K18 exhibited lower FOXD3 expression than the Nthy-ori-3-1 normal thyroid cell line. FOXD3 downregulation in ATC cell lines promoted invasiveness and epithelial-to-mesenchymal transition (EMT) and decreased cellular apoptosis. FOXD3 silencing also enhanced p-ERK levels in the ATC cell lines, suggesting it negatively regulated MAPK/ERK signaling. Silencing FOXD3 in SW1736 cells also led to generation of larger xenograft tumors with high p-ERK and low E-cadherin levels. Moreover, human ATC samples showed lower FOXD3 and higher p-ERK levels than samples of normal thyroid tissue. These findings demonstrate that FOXD3 acts as a tumor suppressor during anaplastic thyroid carcinogenesis and highlight its potential for clinical application.
Insights
Forkhead box D3 (FOXD3) acts as a tumor suppressor in anaplastic thyroid cancer (ATC). Lowering FOXD3 expression promotes cancer invasiveness and tumor growth, suggesting FOXD3 as a potential therapeutic target for ATC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Anaplastic thyroid cancer (ATC) is an aggressive malignancy with a poor prognosis.
- The transcription factor Forkhead box D3 (FOXD3) has been implicated in various cancers.
- The specific role of FOXD3 in ATC pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the antitumorigenic role of FOXD3 in anaplastic thyroid cancer.
- To determine the effect of FOXD3 expression levels on ATC cell behavior and signaling pathways.
- To assess the clinical relevance of FOXD3 in human ATC samples.
Main Methods:
- Comparison of FOXD3 expression in ATC cell lines (SW1736, K18) and normal thyroid cells (Nthy-ori-3-1).
- Assessment of invasiveness, epithelial-to-mesenchymal transition (EMT), and apoptosis following FOXD3 manipulation.
- Analysis of MAPK/ERK signaling pathway components (p-ERK) and E-cadherin levels.
- Xenograft tumor models in mice to evaluate the in vivo effect of FOXD3 silencing.
- Examination of FOXD3 and p-ERK expression in human ATC and normal thyroid tissues.
Main Results:
- ATC cell lines exhibited significantly lower FOXD3 expression compared to normal thyroid cells.
- FOXD3 downregulation promoted invasiveness and EMT while reducing apoptosis in ATC cells.
- FOXD3 silencing led to increased p-ERK levels, indicating negative regulation of the MAPK/ERK pathway.
- In vivo, FOXD3 silencing in SW1736 xenografts resulted in larger tumors with elevated p-ERK and reduced E-cadherin.
- Human ATC samples showed decreased FOXD3 and increased p-ERK levels relative to normal thyroid tissue.
Conclusions:
- FOXD3 functions as a tumor suppressor in anaplastic thyroid cancer.
- FOXD3 downregulation contributes to ATC progression by promoting invasiveness and activating MAPK/ERK signaling.
- FOXD3 represents a potential therapeutic target for clinical intervention in anaplastic thyroid cancer.