The Impact Of Sphingosine Kinase-1on The Prognosis Of Patients With Hepatocellular Carcinoma

Purpose:The present study was to investigate the clinical significant of sphingosine kinase-1(SPHK1), an oncoenzyme, in the development and progression of hepatocellular carcinoma with Portal Vein Tumor Thrombus(PVTT).Methods:mRNA and protein levels of SPHK1expression in the human HCC cell line Hep3B, PVTT cell line CSQT-2, and paired PVTT lesions,HCC and the adjacent noncancerous tissues were examined using gene expression profiling, RT-PCR and immunohistochemistry. We silenced SPHK1expression in CSQT-2cells using artificial microRNA (miRNA)-mediated RNA interference (RNAi) and examined the proliferation and immigration of SPHK1-silenced CSQT-2cells. Immunohistochemistry was employed to analyze SPHK1expression in256clinicopathologically characterized HCC cases. The Cox regression model was used to perform multivariate analysis to determine the independent factors on survival and recurrence.Result:Levels of SPHK1mRNA were higher in CSQT-2cells than in Hep3B cells in the gene expression profiling. SPHK1mRNA and protein level were up-regulated in the paired PVTT and HCC tissues compared with that in adjacent noncancerous tissues. SPHK1knockdown significantly inhibited the proliferation and immigration of PVTT cells. HCC tissues from183of256(71.5%) patients revealed high level of SPHK1protein expression in HCC contrast to the undetectable or marginally detectable expression of SPHK1in the adjacent noncancerous liver tissues. Further, multivariate analysis suggested that SPHK1expression was an independent factor affecting survival (hazard ratio [HR]1.799,95%confidence interval [CI]1.337-2.368, P<0.001) and recurrence (HR1.451,95%CI 1.087-1.935, P=0.011). In the PVTT I and II stage, overexpression of SPHKl could have shorter time to recurrence and survival than those whose tumors had decreased expression of this molecule in PVTT I and II stage, respectively.Conclusions:SPHK1has an important role in the proliferation and immigration in CSQT-2cells. SPHK1overexpression in HCC is strongly correlated with worse surgical outcome, and this molecule likely provides a more precise prognostic predictor in PVTT I and Ⅱ stage...