Sphingosine kinase 1 is a reliable prognostic factor and a novel therapeutic target for uterine cervical cancer

Abstract

// Hyun-Soo Kim 1, * , Gun Yoon 2, * , Ji-Yoon Ryu 3, * , Young-Jae Cho 3 , Jung-Joo Choi 3 , Yoo-Young Lee 3 , Tae-Joong Kim 3 , Chel-Hun Choi 3 , Sang Yong Song 4 , Byoung-Gie Kim 3 , Duk-Soo Bae 3 , Jeong-Won Lee 3, 5 1 Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea 2 Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan-si, Gyeongsangnam-do, Republic of Korea 3 Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 4 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 5 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Jeong-Won Lee, e-mail: garden.lee@samsung.com Keywords: Pathology Section, sphingosine kinase 1, cervical cancer, progression, prognosis, FTY720 Received: June 17, 2015      Accepted: July 11, 2015      Published: July 28, 2015 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.