Sphingosine kinase 2 in sexual dimorphism of hepatocellular carcinoma

项目摘要 肝细胞癌（HCC）是全球范围内癌症相关死亡的第三大原因， 由于地方性肥胖，发病率正在增加。HCC发病率中存在性别二态性，因为女性具有 发生HCC的风险明显低于男性。然而，HCC性别分化的分子机制 二型性仍然不清楚，阻碍了对这种疾病更好的治疗的发展。这项建议会 利用我们开发的饮食诱导NASH进展为HCC的新模型， 在人类疾病中观察到的生理、代谢、组织学和转录组学变化，以检查 鞘氨醇激酶2（SphK 2）以前未被认识到的作用，一种调节神经元平衡的酶， 生物活性鞘脂代谢物，鞘氨醇-1-磷酸（S1 P）和神经酰胺， HCC。与人类相似，我们发现，在这种饮食中，野生型雄性小鼠，而不是雌性小鼠，会发展HCC。 引人注目的是，SphK 2基因敲除的雄性小鼠肿瘤发病率降低，而在雌性小鼠中， 仅在SphK 2敲除小鼠中产生。因此，我们认为SphK 2在性行为中起着关键作用。 HCC的二型性。我们将检验SphK 2保护女性免受HCC的中心假设， 在不同的肝亚细胞中通过几种相互不排斥的机制促进其在雄性中的表达。 细胞器目的1将研究肝脏SphK 2在促进男性HCC的关键信号通路中的作用 和目标2将定义SphK 2在介导耐药性的细胞核和线粒体机制中的作用。 女性患HCC我们的建议利用独特的动物模型和最先进的技术来识别新的 SphK 2调节的分子机制参与饮食诱导的NASH进展中的性别差异， HCC，并且对于现在在临床试验中使用SphK 2抑制剂也具有翻译意义。本研究将 从而更好地了解HCC的性别差异，这对于个性化治疗策略非常重要。 毁灭性的疾病

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide and its incidence is increasing due to endemic obesity. Sexual dimorphism exists in HCC incidence as women have a significantly lower risk for developing HCC than men. However, the molecular mechanisms of HCC sexual dimorphism remain unclear, hindering development of better therapies for this disease. This proposal will utilize a new model that we developed of diet-induced progression of NASH to HCC that recapitulates key physiological, metabolic, histologic and transcriptomic changes observed in the human disease to examine previously unrecognized roles of sphingosine kinase 2 (SphK2), an enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in sexual dimorphism of HCC. Similar to humans, we found that on this diet, wild-type male mice, but not females, develop HCC. Strikingly, SphK2 knockout male mice have reduced tumor incidence, whereas in females, liver cancer developed only in SphK2 knockout mice. Thus, we propose that SphK2 plays a critical role in sexual dimorphism of HCC. We will test the central hypothesis that SphK2 protects females from HCC, while promoting it in males through several mutually non-exclusive mechanisms in distinct hepatic subcellular organelles. Aim 1 will examine the role of liver SphK2 in key signaling pathways that promote HCC in males and Aim 2 will define the role of SphK2 in nuclear and mitochondrial mechanisms mediating resistance of females to HCC. Our proposal utilizes a unique animal model and state-of-the-art techniques to identify novel SphK2-regulated molecular mechanisms involved in sexual disparity in diet-induced progression of NASH to HCC, and also has translational implications for the use of SphK2 inhibitors now in clinical trials. This study will lead to better understanding of sex differences in HCC important for personalized treatment strategies for this devastating disease.