sphingosine-kinase and Nasopharyngeal-Neoplasms

Sphingosine kinase 1 (SPHK1) has been shown to be involved in the progression of various types of human cancers. We previously demonstrated that SPHK1 is overexpressed and associated with clinical stage, locoregional recurrence, distant metastasis and poor prognosis in nasopharyngeal carcinoma (NPC). However, the biological roles involving SPHK1 and its potential usefulness as a therapeutic target in NPC remain unknown. In this study, Blocking SPHK1 using siRNA or FTY720 (a SPHK1 inhibitor) significantly reduced proliferation and migration and increased cell cycle arrest and apoptosis in NPC cells. FTY720 also decreased SPHK1 activity, and overexpressing SPHK1 abrogated the FTY720-induced effects on cell viability. In addition, FTY720 sensitized NPC cells to radiotherapy by inhibiting SPHK1 activity in vitro and in vivo. Furthermore, high SPHK1 expression was associated with increased Ki-67 and p-Akt and decreased caspase-3 expression in human NPC specimens. These data suggest that SPHK1 might be a potential therapeutic target for NPC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemoradiotherapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Fingolimod Hydrochloride; Humans; Ki-67 Antigen; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; RNA Interference; Signal Transduction; Time Factors; Transfection; Xenograft Model Antitumor Assays

It has been reported that sphingosine kinase 1 (SPHK1), an oncogenic enzyme, was involved in the development and progression of a number of human cancers. However, the role of SPHK1 in nasopharyngeal carcinoma (NPC) is largely unknown. The present study aimed to characterize the expression of SPHK1 in human NPC and evaluate its clinical significance. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blot analyses showed that the expression of SPHK1 mRNA and protein in NPC specimens was significantly higher than that in non-tumorous nasopharyngeal mucosa biopsies. Immunohistochemistry (IHC) was conducted to characterize the expression pattern of SPHK1 in 142 archived paraffin-embedded NPC specimens. Statistical analyses revealed that high levels of SPHK1 expression were associated with the clinical stages, locoregional recurrence and distant metastasis of NPC. NPC patients with high levels of SPHK1 expression had shorter survival time, whereas those with lower levels of SPHK1 expression survived longer. Moreover, multivariate analysis suggested that SPHK1 up-regulation was an independent prognostic factor for NPC. Our results suggest for the first time that SPHK1 is involved in the development and progression of NPC, which can be used as a useful prognostic marker for NPC patients and may be an effective target for treating NPC.

Topics: Base Sequence; DNA Primers; Female; Humans; Male; Middle Aged; Nasopharyngeal Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Prognosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction