Identification of Sphingosine Kinase 1 as a Novel Protein Regulated by High Molecular Weight Hyaluronan in Ovarian Cancer

ABSTRACT

The effects of hyaluronan (HA) in cancer are widely studied; however, the role of different molecular weight HA is poorly understood. Identifying novel proteins regulated by different molecular weight HA may highlight novel therapeutic targets. Proteomics analysis was performed to identify novel proteins regulated by different molecular weight HA (27, 183 and 1000 kDa) in ES‐2 ovarian cancer cells over‐expressing Notch3 intra‐cellular domain. Our analyses identified sphingosine kinase 1 (SPHK1), a novel protein regulated by 183‐ and 1000‐kDa HA. Utilising online databases and high‐grade serous ovarian cancer (HGSOC) patient tissue microarray cohorts, we assessed the relationship between SPHK1 expression and ovarian cancer metastasis, recurrence and patient outcome. We assessed the effects of the HA synthesis inhibitor 4‐methylumbelliferone (4‐MU) on SPHK1 expression in ovarian cancer cells and HGSOC patient tissues using ex vivo tissue explant assays. SPHK1 was significantly increased in ovarian cancer compared to normal tissues, elevated in metastatic and recurrent HGSOC tissues and associated with poor patient outcome. 4‐MU significantly inhibited SPHK1 expression in ovarian cancer cells (ES‐2, CaOV3 and A2780) and HGSOC patient tissues. This study highlights a link between HA and SPHK1 expression in ovarian cancer. Our findings confirm an adverse effect on ovarian cancer prognosis. SPHK1 constitutes a novel promising target against ovarian cancer that warrants further investigation.