Sphingosine kinase 2 in sexual dimorphism of hepatocellular carcinoma

项目总结 肝细胞癌是全球癌症相关死亡的第三大原因，其 由于地方性肥胖，发病率正在上升。在肝细胞癌发病率中存在性别二型性，因为女性有 与男性相比，患肝癌的风险显著降低。然而，关于肝细胞癌性分化的分子机制 二型性仍然不清楚，阻碍了对这种疾病更好的治疗方法的开发。这项提议将 利用我们开发的饮食诱导NASH进展为肝细胞癌的新模型，概括了关键 在人类疾病中观察到生理、代谢、组织学和转录的变化来检查 鞘氨醇激酶2(SphK2)是一种调节细胞间平衡的酶，以前未被发现其作用 神经鞘糖脂代谢产物-1-磷酸鞘氨醇(S1P)和神经酰胺在猪性二型性中的作用 肝细胞癌。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，会患上肝癌。 引人注目的是，SphK2基因敲除的雄性小鼠降低了肿瘤发病率，而雌性小鼠患上了肝癌 仅在SphK2基因敲除小鼠中发育。因此，我们认为SphK2在性行为中起着关键作用。 肝细胞癌的二型性。我们将检验核心假设，即SphK2保护女性免受肝癌的侵袭，而 在不同的肝脏亚细胞中通过几种相互非排斥的机制促进雄性 细胞器。目标1将研究肝脏SphK2在促进男性肝癌的关键信号通路中的作用 目标2将定义SphK2在核和线粒体机制中的作用，这些机制介导了 女性去肝细胞癌。我们的建议利用一种独特的动物模型和最先进的技术来识别新的 SphK2调控的分子机制参与饮食诱导的NASH进展中的性别差异 并对SphK2抑制剂目前在临床试验中的使用具有翻译意义。这项研究将 有助于更好地了解肝细胞癌的性别差异，这对个体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.