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.

项目摘要肝细胞癌（HCC）是全球癌症与癌症相关死亡及其的第三主要原因由于地方性肥胖，发病率正在增加。性二态性存在于HCC发病率中，因为女性有一个与男性相比，开发HCC的风险要大大低。但是，HCC性的分子机制二态性仍然不清楚，阻碍了该疾病更好的疗法的发展。该提议将利用我们开发了一种新的模型，该模型是通过饮食引起的NASH向HCC进行的，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以检查鞘氨醇激酶2（SPHK2）的先前未识别的作用，一种调节平衡的酶生物活性鞘脂代谢产物，鞘氨酸1-磷酸盐（S1P）和神经酰胺，在性二态性中 HCC。与人类类似，我们发现，在这种饮食中，野生型雄性小鼠，而不是女性，会发展HCC。令人惊讶的是，SPHK2基因敲除雄性小鼠的肿瘤发病率降低，而在女性中，肝癌仅在SPHK2敲除小鼠中开发。因此，我们建议SPHK2在性中起着至关重要的作用 HCC的双态性。我们将检验中心假设，即SPHK2保护女性免受HCC的侵害，而通过在不同的肝亚细胞中的几种相互非排斥的机制中促进男性细胞器。 AIM 1将检查肝脏SPHK2在促进男性HCC的关键信号通路中的作用 AIM 2将定义SPHK2在核和线粒体机制中的作用，从而介导的抗性女性到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颖 SPHK2调节的分子机制参与性差异的饮食诱导的NASH进展 HCC，并且对现在在临床试验中使用SPHK2抑制剂具有转化含义。这项研究会使对HCC的性别差异更好地理解这对于个性化治疗策略很重要毁灭性疾病。