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

Abstract

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.

Mechanisms of Arachidonic Acid In Vitro Tumoricidal Impact

“…Numerous studies have documented the preponderant role of SM in cancer initiation, progression, and metastasis (reviewed in refs. [ 26 , 34 , 35 , 36 , 37 ]). Yet, few studies have examined the tumor cell surface membrane SM content and properties, despite the fact that tumor cell increased SM (d35:1) content was recently proposed as the most prominent and reliable predictor for lung adenocarcinoma recurrence after surgery [ 38 ].…”

“…In addition to the potential of exposure to otherwise hidden surface membrane molecules that would be invaluable in in vivo settings [ 25 , 26 , 60 ], ARA elicited a remarkable accumulation of Cer at the cell surface and cytosol. Ceramide accumulation at both the cell surface [ 64 , 65 ] and the cytosol plays a preponderant role in mediating physiological and pharmacologically stimulated apoptosis, a ground for considering Cer a tumor-suppressor lipid [ 35 , 36 , 37 , 66 ]. Contrary to previous studies [ 13 , 14 , 18 , 19 , 20 , 21 ], the suppression of tumor cell proliferation and viability following ARA exposure and Cer accumulation may not be ascribed to the induction of ROS release or caspase 3/7 activation.…”

An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma

“…The solvent pair included solvent A (100% H2O, 0.1% FA and 2 mM NH 4 COO − ) and solvent B (100% MeOH, 0.1% FA and 2 mM NH 4 COO − ) with a flow rate at 0.3 mL/min (80% B at the start). Cholesterol and its deuterated standard were separated on an Eclipse Plus C8 column (Agilent), and peaks were integrated with TraceFinder 5.1 (Thermo Fisher, Waltham, USA) using the daughter ion at m/z 161.1 (Figure 2B,C) (66).…”

Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses

“…They are synthesized in the endoplasmic reticulum by serine palmitoyl transferase (SPT), while further reactions lead to the formation of ceramides [ 116 ]. Ceramides are considered anti-cancer factors promoting apoptosis and cell cycle arrest [ 117 , 118 ] and are typically reduced in human HCC [ 119 , 120 , 121 , 122 , 123 , 124 , 125 ]. Furthermore, ceramides may be converted into more complex sphingolipids, such as sphingomyelin (SM), sphingosine 1-phosphate (S1P) and glucosylceramides (GlcCer) [ 93 ] which are considered pro-tumoral factors and whose production is enhanced during HCC pathogenesis [ 126 , 127 , 128 , 129 , 130 , 131 , 132 ].…”