The key finding of the present study is that the elevated expression of SPHK1 protein is correlated with a poor prognosis and reduced survival of SGC patients, suggesting that SPHK1 is a potential independent prognostic factor for SGC. We found that SPHK1 is upregulated in clinical SGC tissues at both the mRNA and protein levels compared with normal salivary gland tissues. Furthermore, statistical analysis of the immunohistochemical results revealed that the expression level of SPHK1 protein is significantly correlated with SGC clinical characteristics, including clinical stage, TNM classification and pathological differentiation. Moreover, those SGC patients who do not receive adjuvant therapy and who exhibit high SPHK1 expression have a significantly lower overall survival rate compared with those with low SPHK1 expression, indicating that SPHK1 expression might represent a valuable predictor for adjuvant therapy for SGC patients.
Owing to the rarity and histological diversity of SGC, the clinical judgments regarding diagnosis and treatment, as well as the prognosis, always present considerable difficulty [1, 2, 4, 5]. Multiple molecular markers have been shown to be associated with the progression and development of SGC. Several groups have demonstrated that HER2/neu is overexpressed at both the protein and mRNA levels in SGCs, ACCs, and MECs [28–31]. Further studies have shown that the high HER2/neu expressing patients with ACC have a significantly shorter disease-free interval compared to those with low HER2/neu expression . Moreover, the expression of HER-2/neu is correlated with local disease recurrence, distant disease metastasis, and overall survival of different histological types in SGC patients [33–36]. In addition, the expression of mutated tumor suppressor gene p53 (in which mutations occur most frequently in exons 7 and 8) has been shown to be associated with the relapse, M classification, and poor prognosis of SDC patients . H-ras mutations, found in various solid tumor types, have also been demonstrated to occur frequently in SGC and are positively correlated with the tumor grade of MECs [38, 39]. Moreover, Lequerica-Fernández and colleagues reported that VEGF is upregulated in 62% of SGC tissues. Further, the expression of VEGF is significantly correlated with lymph node metastasis (P < 0.005), clinical stage (P < 0.02), and disease-specific survival (P < 0.01), suggesting that VEGF might contribute to the progression and development of SGC . However, none of these studies established whether these biomarkers could be used as treatment (adjuvant therapy) predictors or indicators to SGC patients. In the current study, we found that the cumulative 5-year survival rate of patients with high SPHK1 expression but without adjuvant therapy was only 45.1% (95% confidence interval, 0.336-0.566). However, it increased to 79.9% (95% confidence interval, 0.712-0.891) in the low SPHK1 expression group even without adjuvant therapy. These results indicate that SPHK1 expression might be a valuable clinical predictor of adjuvant therapy to SGC patients. Furthermore, statistical analysis revealed no difference in the length of survival time between the low and high SPHK1-expressing patients receiving adjuvant therapy, indicating that SPHK1 expression might also represent a valuable clinical indicator of adjuvant therapy to SGC patients. Meanwhile, we found that the patients with tumors exhibiting low SPHK1 expression and in the group with adjuvant therapy had lower overall survival rates compared with those without adjuvant therapy, which suggested that the adjuvant therapy is not suitable to the patient with tumors exhibiting low SPHK1 expression.
Recently, accumulating evidence has suggested that SPHK1 functions as an onco-enzyme that is closely involved in carcinogenesis [20, 41, 42]. Numerous studies have demonstrated that upregulation of SPHK1 can promote cell proliferation and enhance the resistance to apoptosis induced by different stimuli, and that this upregulation is linked to the failure of clinical cancer therapies, such as chemotherapy and radiotherapy [14, 15, 18–21]. Consistent with these observations, SPHK1 mRNA and protein levels have been found to be significantly elevated in various tumor types [22–26], which prompted us to ask whether the expression of SPHK1 is upregulated and clinically associated with the progression of SGC. To address this question, we examined the expression of SPHK1 under 3 different circumstances, namely, in normal salivary gland and fresh-frozen SGC tissues, in paired primary SGC tissue and adjacent noncancerous tissue, and in a large cohort of paraffin-embedded SGC tissues. Our data showed that the upregulation of SPHK1 mRNA and protein is a universal and frequent event in human SGC tissues, which indicates that SPHK1 overexpression might be associated with the development and progression of SGC. Importantly, 154 (96.9%) of 159 paraffin-embedded archived SGC specimens, including 9 histological types, exhibited positive staining for SPHK1 in the tumor cells, whereas the adjacent noncancerous cells and normal salivary gland tissue expressed little, if any, SPHK1. Furthermore, statistical analysis of the relationship between SPHK1 staining and the clinicopathological characteristics of the patients revealed a significant correlation between SPHK1 expression and the clinical stage, TNM classification, and pathological differentiation of SGC, further supporting the notion that SPHK1 might play a role in the progression of SGC. It is particularly noteworthy that high SPHK1 expression is associated with a shorter survival time. The cumulative 5-year survival rate was 93.4% (95% confidence interval, 0.854-0.914) in the low SPHK1 expression group, whereas it was only 46.3% (95% confidence interval, 0.369-0.573) in the high SPHK1 expression group, suggesting the possibility that SPHK1 can be used as a predictor for patient prognosis and survival.