sphingosine-kinase and Mouth-Neoplasms

Sphingosine-1-phosphate (S1P) signaling has been widely explored as a therapeutic target in cancer. Sphingosine kinase 2 (SK2), one of the kinases that phosphorylate sphingosine, has a cell type and cell location-dependent mechanism of action, so the ability of SK2 to induce cell cycle arrest, apoptosis, proliferation, and survival is strongly influenced by the cell-context. In contrast to SK1, which is widely studied in different types of cancer, including head and neck cancer, the role of SK2 in the development and progression of oral cancer is still poorly understood. In order to elucidate SK2 role in oral cancer, we performed the overexpression of SK2 in non-tumor oral keratinocyte cell (NOK SK2) and in oral squamous cell carcinoma (HN12 SK2), and RNA interference for SK2 in another oral squamous cell carcinoma (HN13 shSK2). In our study we demonstrate for the first time that accumulation of SK2 can be a starting point for oncogenesis and transforms a non-tumor oral keratinocyte (NOK-SI) into highly aggressive tumor cells, even acting on cell plasticity. Furthermore, in oral metastatic cell line (HN12), SK2 contributed even more to the tumorigenesis, inducing proliferation and tumor growth. Our work reveals the intriguing role of SK2 as an oral tumor promoter and regulator of different pathways and cellular processes.

Topics: Autophagy; Carcinogenesis; Carcinoma, Squamous Cell; Cell Proliferation; Cell Transformation, Neoplastic; Head and Neck Neoplasms; Humans; Keratinocytes; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck

Metabolic disorders are significant in the occurrence and development of malignant tumors. Changes of specific metabolites and metabolic pathways are molecular therapeutic targets. This study aims to determine the metabolic differences between oral squamous cell carcinoma (OSCC) tissues and paired adjacent noncancerous tissues (ANT) through liquid chromatography-mass spectrometry (LC-MS). SPHK1 is a key enzyme in sphingolipid metabolism. This study also investigates the potential role of SPHK1 in OSCC.. This study used LC-MS to analyze metabolic differences between OSCC tissues and paired ANT. Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) were applied to explain the significance of phospholipid metabolism pathways in the occurrence and development of OSCC. Through further experiments, we confirmed the oncogenic phenotypes of SPHK1 in vitro and in vivo, including proliferation, migration, and invasion.. The sphingolipid metabolic pathway was significantly activated in OSCC, and the key enzyme SPHK1 was significantly upregulated in oral cancer tissues, predicting poor OSCC prognosis. In this study, SPHK1 overexpression was associated with high-grade malignancy and poor OSCC prognosis. SPHK1 targeted NF-κB by facilitating p65 expression to regulate OSCC tumor progression and promote metastasis.. This study identified metabolic differences between OSCC and paired ANT, explored the carcinogenic role of overexpressed SPHK1, and revealed the association of SPHK1 with poor OSCC prognosis. SPHK1 targets NF-κB signaling by facilitating p65 expression to regulate tumor progression and promote tumor metastasis, providing potential therapeutic targets for diagnosing and treating oral tumors.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Mouth Neoplasms; NF-kappa B; Phospholipids; Phosphotransferases (Alcohol Group Acceptor); Sphingolipids; Squamous Cell Carcinoma of Head and Neck

The expression of sphingosine kinase-1 (SphK1) has been reported in several cancers. However, the exact roles of SphK1 in cancer progression still remain unknown. The aim of the present study was to investigate SphK1 expression in oral squamous cell carcinoma (OSCC) and clarify the involvement of SphK1 in the proliferation and invasiveness of OSCC and its prognostic implications.. Expression of SphK1, E-cadherin, vimentin, and Ki-67 were examined in 69 OSCC tissues immunohistochemically, as well as by western blot, and correlations between their expression and relationships with tumor invasiveness and prognosis were analyzed.. SphK1 was expressed in the tumor cells of 38 of 69 OSCCs, particularly at the invasion front. Patients with OSCCs with high SphK1 expression showed higher invasive grades and unfavorable survival rates. SphK1 expression correlated with acquisition of vimentin expression and loss of E-cadherin expression; there was no significant difference in Ki-67 labeling indices between OSCCs with high and low SphK1 expression.. These results demonstrate the involvement of SphK1 in the invasiveness of OSCC and in unfavorable prognosis, indicating its role in the epithelial-mesenchymal transition of OSCC cells.

Topics: Aged; Aged, 80 and over; Blotting, Western; Carcinoma, Squamous Cell; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Male; Middle Aged; Mouth Neoplasms; Multivariate Analysis; Neoplasm Invasiveness; Phosphotransferases (Alcohol Group Acceptor); Prognosis

We have determined the gene expression of sphingosine-1-phosphate (S1P) metabolizing enzymes (SphK1, SphK2, SGPL1, SGPP1, SGPP2, PPAP2A, PPAP2B, and PPAP2C) by quantitative real-time polymerase chain reaction in tumor tissues and adjacent normal tissues of 50 oral squamous cell carcinoma (OSCC) patients. Expression of SphK1 and SGPP1 genes was up-regulated significantly in 70% and 75% OSCC tumors respectively. Importantly, expression of SphK2 and PPAP2B was down-regulated in the tumor tissues of 70% OSCC patients. Expression of SphK2 and PPAP2B negatively correlated with tumor-node-metastasis (TNM) staging and tumor volume respectively. Furthermore, LPP1 is an independent predictor of TNM staging and lymph node ratio.

Topics: Adult; Aged; Female; Humans; Lip Neoplasms; Lysophospholipids; Male; Membrane Proteins; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Phosphatidate Phosphatase; Phosphoric Monoester Hydrolases; Phosphotransferases (Alcohol Group Acceptor); Real-Time Polymerase Chain Reaction; RNA, Messenger; Sphingosine; Tongue Neoplasms; Young Adult

Oral squamous cell carcinoma (OSCC) is a lethal disease with a 5-year mortality rate of around 50%. Molecular targeted therapies are not in routine use and novel therapeutic targets are required. Our previous microarray data indicated sphingosine 1-phosphate (S1P) metabolism and signalling was deregulated in OSCC. In this study, we have investigated the contribution of S1P signalling to the pathogenesis of OSCC. We show that the expression of the two major enzymes that regulate S1P levels were altered in OSCC: SPHK1 was significantly upregulated in OSCC tissues compared to normal oral mucosa and low levels of SGPL1 mRNA correlated with a worse overall survival. In in vitro studies, S1P enhanced the migration/invasion of OSCC cells and attenuated cisplatin-induced death. We also demonstrate that S1P receptor expression is deregulated in primary OSCCs and that S1PR2 is over-expressed in a subset of tumours, which in part mediates S1P-induced migration of OSCC cells. Lastly, we demonstrate that FTY720 induced significantly more apoptosis in OSCC cells compared to non-malignant cells and that FTY720 acted synergistically with cisplatin to induce cell death. Taken together, our data show that S1P signalling promotes tumour aggressiveness in OSCC and identify S1P signalling as a potential therapeutic target.

Topics: Aldehyde-Lyases; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Cell Movement; Cell Survival; Cisplatin; Drug Synergism; Female; Fingolimod Hydrochloride; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Lysophospholipids; Male; Middle Aged; Mouth Neoplasms; Phenotype; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors