Abstract
Sphingosine kinase 1 (SPHK1), an oncogenic kinase, has previously been found to be upregulated in various types of human malignancy and to play a crucial role in tumor development and progression. Although SPHK1 has gained increasing prominence as an important enzyme in cancer biology, its potential as a predictive biomarker and a therapeutic target in cervical cancer remains unknown. SPHK1 expression was examined in 287 formalin-fixed, paraffin-embedded cervical cancer tissues using immunohistochemistry, and its clinical implications and prognostic significance were analyzed. Cervical cancer cell lines including HeLa and SiHa were treated with the SPHK inhibitors SKI-II or FTY720, and effects on cell survival, apoptosis, angiogenesis, and invasion were examined. Moreover, the effects of FTY720 on tumor growth were evaluated using a patient-derived xenograft (PDX) model of cervical cancer. Immunohistochemical analysis revealed that expression of SPHK1 was significantly increased in cervical cancer compared with normal tissues. SPHK1 expression was significantly associated with tumor size, invasion depth, FIGO stage, lymph node metastasis, and lymphovascular invasion. Patients with high SPHK1 expression had lower overall survival and recurrence-free survival rates than those with low expression. Treatment with SPHK inhibitors significantly reduced viability and increased apoptosis in cervical cancer cells. Furthermore, FTY720 significantly decreased in vivo tumor weight in the PDX model of cervical cancer. We provide the first convincing evidence that SPHK1 is involved in tumor development and progression of cervical cancer. Our data suggest that SPHK1 might be a potential prognostic marker and therapeutic target for the treatment of cervical cancer.
Highlights
Cervical cancer is one of the most common malignant neoplasms worldwide, and is responsible for the death of thousands of women every year [1, 2]
Immunoreactivity for Sphingosine kinase 1 (SPHK1) was mainly localized in the cytoplasm of cancer cells, which is consistent with previous studies on SPHK1 expression in other types of human cancer [7, 10, 12, 16, 21, 22]
Consistent with previous reports [7, 11, 16, 22,23,24], this study showed that the expression of SPHK1 is increased in both cervical cancer cell lines and tissues
Summary
Cervical cancer is one of the most common malignant neoplasms worldwide, and is responsible for the death of thousands of women every year [1, 2]. There is increasing evidence that early detection of cervical cancer has reduced mortality, the prognosis of advanced or recurrent cervical cancer remains very poor. Current treatment for cervical cancer, including surgery with radiation therapy, chemotherapy, and concurrent chemoradiation therapy, can yield cures in 80% to 90% of women with early stage I and II cervical cancer and 60% of those with stage II disease. Cisplatinbased combination chemotherapy, the most commonly used cytotoxic therapy [3], has yielded response rates ranging from 20% to 30% and overall survival of less than 10 months in these patients [4]. Because of the minimal degree of success with cytotoxic therapies and the poor prognosis of patients, there is increased interest in targeted therapeutics for the management of advanced, recurrent, or metastatic cervical cancer
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