Sphingosine Kinase 1 Is Overexpressed and Promotes Proliferation in Human Thyroid Cancer

Abstract

Sphingosine kinase 1 (SphK1), an oncogenic kinase, has been previously found to be elevated in various types of human cancer and play a role in tumor development and progression. Nevertheless, the biological and clinical significance of SphK1 in thyroid cancer is largely unknown. Here, we demonstrate that the expression of SphK1 is generally up-regulated in thyroid cancer and that its expression level is correlated with the degree of thyroid malignancy. Silencing SphK1 by specific RNA interference is able to suppress the proliferation of thyroid cancer cells, and SphK1 expression level is strongly associated with the expression of proliferation cell nuclear antigen in thyroid cancer tissues. Of particular note is that depletion of SphK1 results in dephosphorylation of protein kinase B and glycogen synthase kinase-3β and subsequent inactivation of β-catenin-T-cell factor/lymphoid enhancing factor transcriptional activity. Hence, taken together, our study has identified SphK1 as a proproliferative oncogenic kinase, an Akt/glycogen synthase kinase-3β/β-catenin activator, and probably a biomarker for thyroid cancer as well.

Predictive Value of Sphingosine Kinase 1 Expression in Papillary Thyroid Carcinoma

“…These findings are consistent with our data showing that high sphingosine kinase 1 expression is associated with aggressive oncogenic behavior including tumor multiplicity, extrathyroidal extension, and lymph node metastasis. Our results are also consistent with studies demonstrating an association between elevated sphingosine kinase 1 expression and aggressive oncogenic behavior such as larger tumor size, deeper invasion depth, advanced stage, worse histological differentiation, higher invasiveness, and chemotherapeutic resistance in cancers of the cervix (14), head and neck (37), thyroid (31), salivary duct (32), esophagus (38), colon/rectum (39), and bladder (40).…”

“…They observed that sphingosine kinase 1 promoted cell invasion via interaction between miR-144-3p and fibronectin 1, suggesting a pro-invasive function. Guan et al (31) reported that sphingosine kinase 1 expression in thyroid cancer is up-regulated and associated with expression of proliferating cell nuclear antigen and showed that silencing of sphingosine kinase 1 suppresses proliferation of thyroid cancer cells. Other studies have shown that increased sphingosine kinase 1 expression is associated with lymph node metastasis and distant metastasis of breast cancer (36).…”

“…The degree of sphingosine kinase 1 expression was evaluated by multiplying scores for the proportion of positively stained cancer cells and staining intensity (14,20,31). The proportion of stained cancer cells was scored as: 0, none; 1, 1-9%; 2, 10-49%; 3, ≥50% of all cancer cells.…”

Sphingosine 1-phosphate and human ether-a′-go-go-related gene potassium channels modulate migration in human anaplastic thyroid cancer cells

“…We have previously shown that overexpression of SphK1 in ML-1 thyroid cancer cells enhanced migration of these cells but that in FTC-133 cells, SphK1 overexpression decreased migration (Bergelin et al 2009). Furthermore, in a recent study, SphK1 was shown to be overexpressed in several cell lines, promoting proliferation of these cells (Guan et al 2011). In addition, Guan et al (2011) showed that several thyroid cancers are overexpressing SphK1 and that the overexpression correlates with the degree of malignancy.…”

“…Furthermore, in a recent study, SphK1 was shown to be overexpressed in several cell lines, promoting proliferation of these cells (Guan et al 2011). In addition, Guan et al (2011) showed that several thyroid cancers are overexpressing SphK1 and that the overexpression correlates with the degree of malignancy. As the migration of FTC-133 cells was decreased by S1P, we blocked SphK1 in the C643 cells using the inhibitor SKi.…”