The prognostic and predictive impact of Sphingosine kinase 1 protein expression in patients with non-smallcell lung cancer

Introduction: Sphingosine kinase 1 (SphK-1) is a key regulatory enzyme of sphingolipid metabolism. Spingolipides are a family of membrane lipids. Their metabolites, such as ceramide and sphingosine-1-phosphate (S1P), have been shown to have an opposing effects in cell signaling pathways, including the cancer cell growth and proliferation. These lipid molecules have also been implicated in the mechanism of action of cancer chemotherapeutics. SphK-1 appears to alter the ceramide/S1P balance, and effectively regulates drug-induced apoptosis, and serving as a chemotherapy sensor both in culture and in animal models of various tumors. We aimed to investigate the prognostic and predictive value of SphK1 in non-small cell lung cancer (NSCLC) patients treated by adjuvant and/or neoadjuvant chemotherapy.

Materials and methods: We performed immuno histochemical analysis on tissue microarrays from 201 NSCLCs patient samples. 82 patients were in clinical stage I, 37 in stage II, and 82 in stage IIIa. 49 patients, mostly in stage IIIa had received neoadjuvant chemotherapy, either carboplatin and paclitaxel based, from where 31 were also treated by adjuvant chemotherapy (aCHT). A total of 76 patients had received adjuvant chemotherapy mostly based on a combination of platinum with paclitaxel or navelbin. Cohort of surgically treated patients who received neither adjuvant nor neoadjuvant chemotherapy consisted of 40 patients. Disease-free survival (DFS) was determined as the interval from diagnosis to disease recurrence, with a median of 35 months (25% and 75% quantiles; 11.2 and 94.7 months, respectively). Overall survival (OS) was determined as the time from diagnosis to death (median, 39.8 months; 25% and 75% quantiles, 13.5 and 101.0 months, respectively).

Results: SphK1 protein expression was significantly increased in all types of NSCLC. Log-rank and Kaplan-Meier analysis demonstrated that OS and DFS of patients with high expression of SphK1 in tumors did not significantly differ from that of the low SphK1 expression NSCLC group. However, SphK1 cytoplasmic expression and stage were the predictors of hazard death in patients without prior chemoterapy. Increase in the cytoplasmic expression of SphK1 causes the decrease of hazard of death (HR=0.716; P=0.007; 95% CI [0.563-0.911]). Hazard of death higher in stage III in comparison to I-II (HR=2.95; P<0.001; 95% CI [1.827-4.762]). Significant correlations were also found between the expression of SphK1 and the expression of nestin, asporin and p53.

Conclusions: The results of our study showed that the predictive value of independent SphK1 protein expression is not significant in patients with NSCLC.