Downregulation of Lipid Phosphate Phosphatase 3 correlates with Tumor-Infiltrating Immune Cells in Oral Cancer

Purpose Sphingosine-1-phosphate (S1P), a potent oncogenic lipid. Intracellular levels of S1P are tightly regulated by eight S1P metabolizing enzymes. S1P is synthesized by phosphorylation of sphingosine which is catalyzed by two sphingosine kinases (SphK1 and SphK2). Five lipid phosphatases (two S1P phosphatases and three lipid phosphate phosphatases) reversibly convert S1P back to sphingosine. S1P is ultimately irreversibly degraded by S1P lyase. The role of sphingosine-1-phosphate (S1P) metabolizing enzymes in oral squamous cell carcinoma (OSCC) has not been fully studied. Methods In the current study, we have determined the protein expression of four S1P metabolizing enzymes, namely sphingosine Kinase (SphK) -1, SphK2, S1P phosphatase 1 (SGPP1), and lipid phosphate phosphatase 3 (LPP3) by immunohistochemistry (IHC) and western botting in tumor tissues of 46 OSCC patients and normal oral mucosa (N = 6). Further, we determined the associations of expression of S1P metabolizing enzymes with clinicopathological features of OSCC patients. Results SphK2 and LPP3 exhibit low IRS in OSCC tumors. Importantly, expression of SphK2 and LPP3 was downregulated in malignant cells compared to non-malignant mucosa. Further, LPP3 expression negatively correlated with TNM staging of patients (ρ = -0.307, p = 0.043). Importantly, TCGA analysis revealed that LPP3 expression was positively correlated with infiltration of B cells, neutrophils, macrophages, and dendritic cells in the HNSCC tumors. Conclusion In conclusion, our data show that expression of SphK2 and LPP3 is decreased in OSCC tumors compared to normal mucosa. Thus, LPP3 could represent a potential prognostic marker and therapeutic target for OSCC.

Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

Besides serving as a structural membrane component and intermediate of the glycerolipid metabolism, lysophosphatidic acid (LPA) has a prominent role as a signaling molecule through its binding to LPA receptors at the cell surface. Extracellular LPA is primarily produced from lysophosphatidylcholine (LPC) through the activity of secreted lysophospholipase D, autotaxin (ATX). The degradation of extracellular LPA to monoacylglycerol is mediated by lipid phosphate phosphatases (LPPs) at the cell membrane. This review summarizes and interprets current literature on the role of the ATX-LPA-LPP3 axis in the regulation of energy homeostasis, insulin function, and adiposity at baseline and under conditions of obesity. We also discuss how the ATX-LPA-LPP3 axis influences obesity-related metabolic complications, including insulin resistance, fatty liver disease, and cardiomyopathy.

Abstract 16007: Myeloid-specific Deletion in Lipid Phosphate Phosphatase3 (plpp3) Increases Cardiac Inflammation

Introduction and Hypothesis: Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide. The innate immune response plays a major role in cardiac remodeling after AMI. Lysophosphatidic acid (LPA), produced by autotaxin (ATX) and degraded by Lipid phosphate phosphatase 3 (LPP3), regulates monocytosis and promotes inflammation. However, the role of LPP3 in post-AMI inflammation is not understood. Here, we investigated the possible role of Myeloid-specific Plpp3 KO mice in cardiac and systemic inflammation and resulting in adverse cardiac remodeling post-MI. Methods and Results: To generate mice with Myeloid-specific Plpp3 deletion , female Plpp3 fl/fl mice were crossed to male Plpp3 mice expressing Cre recombinase under the control of the LysM promoter to generate lysm-plpp3. mice. These mice and their littermate control underwent MI or sham surgery. Inflammatory cell content was assessed using flow cytometry and immunohistochemistry. Cardiac function and scar size were assessed by echocardiography and Mason Trichrome staining, respectively. Increased number of Ly6C hi monocytes (CD45 + /Ly6C/G hi /CD115 hi ) and pro-inflammatory macrophages (CD45 + /F4-80 + /CD11b + ) (CD45 + /F4-80 + /CD86 + ), in cardiac tissue of Cre+LysM mice was observed compared to Cre-fl/fl littermate controls during peak post-MI inflammation, as assessed by flow cytometry ( Fig.1A-C ). This increase in inflammatory cells and inflammation may be the consequence of the significant increase in bone marrow and spleen progenitor cell count and proliferation. Moreover, Cre+LysM mice cardiac functional recovery was also reduced significantly ( Fig. 1D-F ) as assessed by echocardiography. Conclusion: Myeloid-specific Plpp3 deletion increases the deleterious effects of inflammation on the ischemic myocardium and ATX/ LPA signaling could represent a novel therapeutic target for future clinical studies of coronary heart diseases.

Lipid Phosphate Phosphatases and Cancer

Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1–3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide spectrum of bioactive lipid phosphates, among which lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are two important extracellular signaling molecules. The LPPs are integral membrane proteins, which are localized on plasma membranes and intracellular membranes, including the endoplasmic reticulum and Golgi network. LPPs regulate signaling transduction in cancer cells and demonstrate different effects in cancer progression through the breakdown of extracellular LPA and S1P and other intracellular substrates. This review is intended to summarize an up-to-date understanding about the functions of LPPs in cancers.