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Updated: Feb 10, 2026
An Orthotopic Mouse Model of Anaplastic Thyroid Carcinoma
Published on: April 17, 2013
SPHK1 promotes metastasis of thyroid carcinoma through activation of the S1P/S1PR3/Notch signaling pathway
Zhijing Zhao1, Junfeng Ma1, Baoquan Hu2
1Thyroid-Breast Surgery Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China.
Abstract:
Thyroid carcinoma is characterized by an aggressive behavior, lack of effective targeted therapies and a high rate of relapse. Sphingosine kinase 1 (SPHK1) has been reported to be a critical regulatory factor in the progression of thyroid carcinoma, but the correlation between SPHK1 and clinical prognosis of patients with thyroid carcinoma has remained to be fully elucidated. The present study aimed to systematically assess the roles of SPHK1 in thyroid carcinoma metastasis and further investigate the possible underlying mechanisms. First, the expression of SPHK1 was detected in tissue samples from 53 thyroid carcinoma patients and in thyroid carcinoma cell lines by reverse transcription-quantitative polymerase chain reaction analysis. Furthermore, the level of phospho-(p)-SPHK1 was immunohistochemically detected in human thyroid carcinoma tissue samples. The activity of SPHK1 was measured with a commercial SPHK1 Activity Assay kit. A sphingosine-1-phosphate (S1P) competitive ELISA kit was used to determine the extracellular S1P levels. The metastatic potential was assessed by a Transwell assay. In addition, the association between SPHK1 and clinicopathological features of the patients was analyzed. The results indicated that the expression of SPHK1 in thyroid carcinoma samples was significantly higher than in paired adjacent normal thyroid tissues. High levels of SPHK1 were positively correlated with poor overall survival and progression-free survival. Downregulation of SPHK1 by lentiviral vector expressing SPHK1 small interfering (si)RNA evidently repressed Notch signaling and reduced the migration and invasion of thyroid carcinoma cells in vitro and in a NOD/SCID mouse model. Furthermore, inhibition of SPHK1 by siRNA or treatment with SPHK1 inhibitor 5C sensitized thyroid carcinoma to cisplatin and doxorubicin. In addition, it was demonstrated that silencing of SPHK1 effectively inhibits processes associated with thyroid carcinoma metastasis through the Notch signaling pathway, and SPHK1 may therefore represent a potential therapeutic target in thyroid carcinoma. In conclusion, the present study indicated that high levels of p-SPHK1 were positively correlated with high levels of S1P which in turn promoted thyroid carcinoma metastasis via the S1P/S1P receptor 3/Notch signaling pathway, suggesting possible prognostic markers and therapeutic targets.
Insights
Sphingosine kinase 1 (SPHK1) promotes thyroid carcinoma metastasis via the S1P/S1P receptor 3/Notch signaling pathway. Inhibiting SPHK1 may offer a new therapeutic strategy for thyroid cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Thyroid carcinoma exhibits aggressive behavior, limited targeted therapies, and frequent relapse.
- Sphingosine kinase 1 (SPHK1) is implicated in thyroid carcinoma progression, but its prognostic role and mechanistic involvement in metastasis require elucidation.
Purpose of the Study:
- To systematically evaluate the role of SPHK1 in thyroid carcinoma metastasis.
- To investigate the underlying molecular mechanisms, including the involvement of the Notch signaling pathway.
- To explore SPHK1 as a potential therapeutic target and prognostic marker.
Main Methods:
- Quantitative reverse transcription PCR and immunohistochemistry to assess SPHK1 expression in patient samples and cell lines.
- SPHK1 activity assays and ELISA to measure SPHK1 activity and extracellular sphingosine-1-phosphate (S1P) levels.
- Transwell assays and a NOD/SCID mouse model to evaluate metastatic potential.
- Lentiviral-mediated SPHK1 small interfering RNA (siRNA) for gene silencing.
Main Results:
- SPHK1 expression was significantly elevated in thyroid carcinoma tissues compared to normal tissues.
- High SPHK1 levels correlated with poorer overall and progression-free survival.
- SPHK1 downregulation repressed Notch signaling, reducing cell migration and invasion in vitro and in vivo.
- SPHK1 inhibition sensitized thyroid carcinoma cells to cisplatin and doxorubicin.
Conclusions:
- Elevated SPHK1 and subsequent high S1P levels promote thyroid carcinoma metastasis through the S1P/S1P receptor 3/Notch signaling pathway.
- SPHK1 inhibition effectively suppresses metastasis and sensitizes cancer cells to chemotherapy.
- SPHK1 represents a promising therapeutic target and prognostic biomarker for thyroid carcinoma.
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