Sphingosine kinase 1 overexpression is associated with poor prognosis and oxaliplatin resistance in hepatocellular carcinoma.

Sphingosine kinase 1 (SphK1) is a tumor-associated protein overexpressed in numerous types of cancer and is involved in the regulation of resistance to multiple chemotherapeutic agents. However, the role of SphK1 in the resistance of hepatocellular carcinoma (HCC) to oxaliplatin remains unclear. In the present study, the transcriptional levels of SphK1 were analyzed in 21 patients with HCC and the SphK1 expression levels were identified to be significantly upregulated in HCC tissue compared with that in adjacent normal tissue samples (P<0.001). High SphK1 expression correlated with shorter overall survival times in patients with HCC (P<0.05). Furthermore, SphK1 expression levels and activity were analyzed in a series of HCC cell lines and they were both demonstrated to be associated with resistance to oxaliplatin. Conversely, the knockdown of SphK1 protein expression resulted in decreased oxaliplatin resistance in SK-Hep1 and HCCLM3 cell lines. In addition, the results of the current study demonstrated that the downregulation of SphK1 decreased the levels of phosphorylated AKT serine/threonine kinase (Akt) and glycogen synthase kinase-3β (GSK3β), suggesting that SphK1 promotes oxaliplatin resistance of HCC cells via modulation of the Akt/GSK3β signaling pathway. To the best of our knowledge, the present study is the first to report that SphK1 is associated with poor prognosis and oxaliplatin resistance in HCC. Thus, the findings of the current study have provided a direction for the identification of novel therapeutic targets for the treatment of HCC.