S1P lyase in colon cancer

结肠癌中的 S1P 裂解酶

• 批准号: 8806359
• 负责人: JULIE D SABA
• 金额: $ 16.65万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8806359
• 关键词: AKT Signaling Pathway; Antidotes; Apoptosis; Azoxymethane; Biological Models; Biology; Bone Marrow; Calcium; Cancer Etiology; Cells; Ceramides; Characteristics; Chemopreventive Agent; Colitis; Colon; Colon Carcinoma; Development; Diet; Disease; Down-Regulation; Embryo; Enterocytes; Enzymes; Epithelial Cells; Exposure to; Family; Fatty acid glycerol esters; Fibroblasts; Genetic Transcription; Goals; Histology; Human; Immune; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Neoplasms; Intestines; Knockout Mice; Lipid Biochemistry; Lipids; Lyase; Malignant Neoplasms; Mediating; Messenger RNA; Metabolism; MicroRNAs; Mitochondria; Molecular Analysis; Molecular Biology; Morbidity - disease rate; Mucous Membrane; Mus; Oncogenic; Oral; Positioning Attribute; Public Health; Regimen; Risk; Rodent Model; Role; SPHK1 enzyme; STAT3 gene; Signal Transduction; Sodium Dextran Sulfate; Sphingolipids; Sphingosine; Testing; Tissues; United States; Veterinary Pathology; Vitamin D; Work; Xenograft Model; adenoma; base; cancer cell; cancer chemoprevention; cancer risk; carcinogenesis; cell transformation; colon cancer cell line; colon carcinogenesis; cytokine; immune function; intestinal epithelium; mortality; mouse model; neoplastic cell; novel; overexpression; prevent; public health relevance; soy; sphingosine 1-phosphate; sphingosine-1-phosphate lyase; transcription factor; tumor; tumor microenvironment; tumorigenesis

DESCRIPTION (provided by applicant): Dietary sphingolipids such as sphingosine and ceramide promote enterocyte turnover and have been shown to protect against intestinal tumorigenesis in mice. However, sphingosine taken up by enterocytes can be phosphorylated by the oncogenic enzyme SphK1, generating sphingosine-1-phosphate (S1P), a mitogenic lipid that inhibits apoptosis and promotes inflammation, transformation and carcinogenesis. Thus, dietary sphingolipids represent a double-edged sword in colon cancer. Elucidating their specific roles in carcinogenesis is a necessary first step to developing sphingolipid-based strategies to lower colon cancer risk. S1P is irreversibly degraded by the enzyme S1P lyase (SPL) which is highly expressed in enterocytes and other cellular compartments of the gut mucosa. We showed previously that SPL is downregulated in ApcMin/+ mouse adenomas and human colon cancers. We now show that SPL is also downregulated in tumors that develop in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice. Thus, SPL downregulation is a common feature of intestinal neoplasia. We generated gut-specific SPL knockout mice (SPLGutKO) and demonstrated that loss of enterocyte SPL expression promotes tumorigenesis in ApcMin/+ mice and enhances colitis, enterocyte proliferation and tumor incidence in AOM/DSS-treated mice. Loss of SPL expression was associated with increased activation of STAT3, a critical regulator of inflammation, carcinogenesis and interactions between tumor cells and the tumor microenvironment or "niche". STAT3 acts as a transcription factor with many mRNA and microRNA targets. STAT3 has also been shown to regulate mitochondrial functions. Importantly, we found that inhibition of STAT3 prevented the ability of SPL disruption to promote tumorigenesis in AOM/DSS and xenograft model systems. In addition to these findings, we recently identified a family of soy-derived sphingolipids called sphingadienes (SDs) with chemopreventive action in mice. SDs promote enterocyte turnover, inhibit STAT3, WNT and AKT signaling pathways and, importantly, induce SPL expression in colon cancer cell lines. Our cumulative findings have led us to propose our central hypothesis, which states that: SPL downregulation promotes colon carcinogenesis through STAT3-dependent mechanisms that influence intestinal epithelial cells and other cellular compartments of the tumor niche. We further propose that SDs serve as an antidote to SPL downregulation by reversing it and its associated effects on colon inflammation and carcinogenesis. To test our hypothesis, we have devised four Specific Aims: 1) To clarify how S1P promotes cell transformation and tumorigenesis; 2) To elucidate the role of SPL in modulating the tumor niche; 3) To establish whether SPL downregulation promotes intestinal tumorigenesis induced by a pro-inflammatory diet; 4) To test whether SDs can reverse SPL downregulation and its associated effects during intestinal tumorigenesis. In accomplishing these aims, we should achieve our two major goals: to elucidate the biology of SPL in colon cancer, and to develop chemopreventive strategies that work by reactivation of SPL.

描述(由申请人提供)：膳食中的鞘磷脂，如鞘氨醇和神经酰胺，促进肠道细胞的更新，并已被证明对小鼠的肠道肿瘤具有保护作用。然而，肠细胞摄取的鞘氨醇可以被致癌酶SphK1磷酸化，产生鞘氨醇-1-磷酸(S1P)，这是一种抑制细胞凋亡并促进炎症、转化和癌症发生的有丝分裂脂。因此，饮食中的鞘脂对结肠癌来说是一把双刃剑。阐明它们在癌症发生中的特定作用是开发基于鞘磷脂的策略以降低结肠癌风险的必要的第一步。S1P被S1P裂解酶(SPL)不可逆地降解，该酶在肠粘膜的肠细胞和其他细胞室中高度表达。我们以前发现SPL在ApcMin/+鼠腺瘤和人类结肠癌中表达下调。我们现在发现，在偶氮甲烷/葡聚糖硫酸钠(AOM/DSS)治疗的小鼠中，SPL也被下调。因此，SPL下调是肠道肿瘤的常见特征。我们建立了肠道特异性SPL基因敲除小鼠(SPLGutKO)，并证明肠细胞SPL表达的缺失促进了ApcMin/+小鼠的肿瘤发生，并增强了AOM/DSS治疗小鼠的结肠炎、肠细胞增殖和肿瘤发病率。SPL表达的缺失与STAT3的激活增加有关，STAT3是炎症、癌症发生以及肿瘤细胞与肿瘤微环境或“生态位”之间相互作用的关键调节因子。STAT3是一种转录因子，具有多个mRNA和microRNA靶点。STAT3也被证明可以调节线粒体的功能。重要的是，我们发现，在AOM/DSS和异种移植模型系统中，抑制STAT3可以阻止SPL中断促进肿瘤发生的能力。除了这些发现外，我们最近还发现了一类大豆衍生的鞘磷脂家族，称为鞘双烯(SDS)，在小鼠身上具有化学预防作用。十二烷基硫酸钠可促进肠上皮细胞的周转，抑制STAT3、WNT和AKT信号通路，更重要的是诱导结肠癌细胞株SPL的表达。我们的累积发现导致我们提出了我们的中心假说，即：SPL下调通过STAT3依赖的机制影响肠道上皮细胞和肿瘤生态位的其他细胞间隔，从而促进结肠癌的发生。我们进一步提出，十二烷基硫酸钠通过逆转SPL下调及其在结肠炎和癌变中的相关作用，作为SPL下调的解毒剂。为了验证我们的假设，我们设计了四个具体的目标：1)阐明S1P是如何促进细胞转化和肿瘤发生的；2)阐明SPL在调节肿瘤生态位中的作用；3)确定SPL下调是否促进了促炎饮食诱导的肠道肿瘤发生；4)测试十二烷基硫酸钠是否可以逆转SPL下调及其在肠道肿瘤发生中的相关作用。为了实现这些目标，我们应该实现我们的两个主要目标：阐明SPL在结肠癌中的生物学作用，以及开发通过重新激活SPL发挥作用的化学预防策略。