Background
Sphingosine-1-phosphate (S1P) is a potent oncogenic
lipid. Intracellular levels of S1P are tightly regulated by eight S1P-metabolizing
enzymes. S1P synthesis is catalyzed by two
sphingosine kinases, i.e.,
sphingosine kinase 1 (SphK1) and
sphingosine kinase 2 (SphK2). Five
lipid phosphatases (two S1P
phosphatases and
lipid phosphate phosphatases (LPPs) 1, 2, and 3) reversibly convert S1P back to
sphingosine. Previously, we have determined the
mRNA expression profile of eight S1P-metabolizing
enzymes in
tumor tissues and adjacent normal tissues from
oral squamous cell carcinoma (OSCC) patients. Except for SphK1, the role of S1P-metabolizing
enzymes in OSCC has been poorly studied. Methods We have determined the
protein expression of four S1P-metabolizing
enzymes (SphK1, SphK2,
sphingosine-1-
phosphate phosphatase 1 (SGPP1), and
lipid phosphate phosphatase 3 (LPP3)) by immunohistochemistry (IHC) in
tumor tissues of 46 OSCC patients. Six subjects with non-dysplastic oral mucosa were also included in the study. The immunoreactivity score (IRS) was calculated for each
protein in every subject. Further, we determined the associations of expression of S1P-metabolizing
enzymes with clinicopathological features of OSCC patients. Results We demonstrate the low IRS for SphK2 and LPP3 in OSCC
tumors. Importantly, expression of SphK2 and LPP3 was downregulated in malignant epithelial cells compared to non-malignant mucosa. Further, LPP3 expression negatively correlated with tumor‑node‑metastasis (TNM) staging of patients (r = -0.307, p = 0.043). Importantly, expression of LPP3 in
tumors was found to be an independent predictor of perinodal extension (b = -0.440, p = 0.009), lymphovascular invasion (b = -0.614, p < 0.001), lymph node ratio (b = 0.336, p = 0.039), and TNM staging (b = -0.364, p = 0.030). Conclusion Taken together, our data show that expression of SphK2 and LPP3 is decreased compared to normal mucosa. Thus, the S1P signaling pathway could represent a potential therapeutic target.