Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein.

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer, the third leading cause of cancer-associated death worldwide. With the increasing prevalence of metabolic conditions, non-alcoholic fatty liver disease (NAFLD) is emerging as the fastest-growing HCC risk factor, and it imposes an additional layer of difficulty in HCC management. Dysregulated hepatic lipids are generally believed to constitute a deleterious environment cultivating the development of NAFLD-associated HCC. However, exactly which lipids or lipid regulators drive this process remains elusive. We report herein that sphingosine kinase 2 (SphK2), a key sphingolipid metabolic enzyme, plays a critical role in NAFLD-associated HCC. Ablation of Sphk2 suppressed HCC development in NAFLD livers via inhibition of hepatocyte proliferation both in vivo and in vitro. Mechanistically, SphK2 deficiency led to downregulation of ceramide transfer protein (CERT) that, in turn, decreased the ratio of pro-cancer sphingomyelin (SM) to anti-cancer ceramide. Overexpression of CERT restored hepatocyte proliferation, colony growth and cell cycle progression. In conclusion, the current study demonstrates that SphK2 is an essential lipid regulator in NAFLD-associated HCC, providing experimental evidence to support clinical trials of SphK2 inhibitors as systemic therapies against HCC.

Exposure to Systemic Immunosuppressive Ultraviolet Radiation Alters T Cell Recirculation through Sphingosine-1-Phosphate.

Systemic suppression of adaptive immune responses is a major way in which UV radiation contributes to skin cancer development. Immune suppression is also likely to explain how UV protects from some autoimmune diseases, such as multiple sclerosis. However, the mechanisms underlying UV-mediated systemic immune suppression are not well understood. Exposure of C57BL/6 mice to doses of UV known to suppress systemic autoimmunity led to the accumulation of cells within the skin-draining lymph nodes and away from non-skin-draining lymph nodes. Transfer of CD45.1+ cells from nonirradiated donors into CD45.2+ UV-irradiated recipients resulted in preferential accumulation of donor naive T cells and a decrease in activated T cells within skin-draining lymph nodes. A single dose of immune-suppressive UV was all that was required to cause a redistribution of naive and central memory T cells from peripheral blood to the skin-draining lymph nodes. Specifically, CD69-independent increases in sphingosine-1-phosphate (S1P) receptor 1-negative naive and central memory T cells occurred in these lymph nodes. Mass spectrometry analysis showed UV-mediated activation of sphingosine kinase 1 activity, resulting in an increase in S1P levels within the lymph nodes. Topical application of a sphingosine kinase inhibitor on the skin prior to UV irradiation eliminated the UV-induced increase in lymph node S1P and T cell numbers. Thus, exposure to immunosuppressive UV disrupts T cell recirculation by manipulating the S1P pathway.

Hollow Mesoporous Silica Nanoparticles with Extra-Large Mesopores for Enhanced Cancer Vaccine.

Owing to the limitations of conventional cancer therapies, cancer immunotherapy has emerged for the prevention of cancer recurrence. To provoke adaptive immune responses that are antigen-specific, it is important to develop an efficient antigen delivery system that can enhance the activation and maturation of the dendritic cells (DCs) in the human body. In this study, we synthesize hollow mesoporous silica nanoparticles with extra-large mesopores (H-XL-MSNs) based on a single-step synthesis from core-shell mesoporous silica nanoparticles with a core composed of an assembly of iron oxide nanoparticles. The hollow void inside the mesoporous silica nanoparticles with large mesopores allows a high loading efficiency of various model proteins of different sizes. The H-XL-MSNs are coated with a poly(ethyleneimine) (PEI) solution to provide an immune adjuvant and change the surface charge of the particles for loading and slow release of a model antigen. An in vitro study using a cancer vaccine based on the PEI-coated H-XL-MSNs with the loading of the model antigen showed an enhanced activation of the DCs. An in vivo study demonstrated that the resulting cancer vaccine increased the antigen-specific cytotoxic T cells, enhanced the suppression of tumor growth, and improved the survival rate after challenging cancer to mice. These findings suggest that these hollow MSNs with extra-large pores can be used as excellent antigen carriers for immunotherapy.