Sphingosine kinase 2 in sexual dimorphism of hepatocellular carcinoma

鞘氨醇激酶2在肝细胞癌性别二态性中的作用

基本信息

批准号：
10521724
负责人：
Christopher D Green
金额：
$ 39.02万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521724
关键词：
Androgen Metabolism Androgen Receptor Androgens Animal Model Binding Cancer Etiology Carcinogens Cell Cycle Cell Nucleus Cells Ceramides Cessation of life Cholesterol Homeostasis Clinical Trials Data Development Diet Disease Enzymes Equilibrium Estrogen Receptor alpha Estrogens Etiology Exhibits Fatty Acids Female Gene Expression Generations Genes Genetic Transcription Hepatic Hepatocarcinogenesis Hepatocyte High Fat Diet Histologic Histone Acetylation Histone Deacetylase Human Incidence Inflammation Isoenzymes Knock-out Knockout Mice Link Lipids Liver Liver Mitochondria Malignant neoplasm of liver Mediating Metabolic Mitochondria Modeling Molecular Mus Nuclear Obesity Oncogenic Organelles Oxidative Stress Pathway interactions Patients Physiological Play Predisposition Primary carcinoma of the liver cells Production Prognosis Publishing Reactive Oxygen Species Regulation Reporting Resistance Respiration Risk Rodent Role Sex Differences Signal Pathway Signal Transduction Signaling Protein Sphingolipids Structure Techniques Testing Testosterone Triglycerides Water Woman c-myc Genes gene repression high risk human disease inhibitor intrahepatic liver cell proliferation male men mitochondrial dysfunction mortality non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel personalized medicine premalignant prohibitin respiratory sex sexual dimorphism sexual disparity sphingosine 1-phosphate sphingosine kinase stem cells sugar transcriptomics treatment strategy tumor tumor initiation tumorigenesis

项目摘要

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.

项目概要肝细胞癌（HCC）是全球癌症相关死亡的第三大原因，其由于地方性肥胖，发病率正在增加。 HCC 发病率存在性别二态性，因为女性有与男性相比，患 HCC 的风险显着降低。然而，HCC发生的分子机制二态性仍不清楚，阻碍了针对这种疾病更好的治疗方法的开发。该提案将利用我们开发的饮食诱导 NASH 进展为 HCC 的新模型，该模型概括了关键在人类疾病中观察到的生理、代谢、组织学和转录组变化来检查鞘氨醇激酶 2 (SphK2) 是一种调节平衡的酶，之前未被认识到其作用生物活性鞘脂代谢物、1-磷酸鞘氨醇 (S1P) 和神经酰胺，在性别二态性中肝癌。与人类类似，我们发现在这种饮食下，野生型雄性小鼠（而非雌性）会患上肝癌。引人注目的是，SphK2 基因敲除的雄性小鼠肿瘤发病率降低，而雌性小鼠肝癌发病率降低仅在 SphK2 敲除小鼠中开发。因此，我们认为 SphK2 在性方面发挥着关键作用。 HCC 的二态性。我们将检验 SphK2 保护女性免受 HCC 的中心假设，而通过不同肝亚细胞中几种相互非排斥的机制在男性中促进它细胞器。目标 1 将检查肝脏 SphK2 在促进男性 HCC 的关键信号通路中的作用目标 2 将定义 SphK2 在介导耐药性的核和线粒体机制中的作用女性患肝癌。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颖的 SphK2 调节的分子机制参与饮食诱导的 NASH 进展中的性别差异 HCC，并且对目前临床试验中使用 SphK2 抑制剂也具有转化意义。这项研究将更好地了解 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。