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）：饮食中的鞘脂，例如鞘氨酸和神经酰胺，可促进肠上皮细胞更新，并已证明可以预防小鼠肠道肿瘤发生。然而，肠肠细胞吸收的鞘氨酸可以被致癌酶SPHK1磷酸化，从而产生鞘氨酸-1-磷酸盐（S1P），这是一种有丝分裂的脂质，抑制凋亡并促进炎症，促进炎症，转化，转化，转化和致癌。因此，饮食中的鞘脂代表结肠癌的双刃剑。阐明其在癌变中的特定作用是制定基于鞘脂的策略以降低结肠癌风险的必要第一步。 S1P被酶S1P裂解酶（SPL）降解，该酶在肠粘膜的肠细胞和其他细胞室中高度表达。我们先前表明，在APCMIN/+小鼠腺瘤和人类结肠癌中SPL被下调。我们现在表明，在硫酸硫酸钠（AOM/DSS）处理的小鼠中，SPL也被下调。因此，SPL下调是肠道肿瘤的常见特征。我们产生了肠道特异性的SPL基因敲除小鼠（Splgutko），并证明肠肠细胞SPL表达的丧失会促进APCMIN/+小鼠的肿瘤发生，并增强结肠炎，肠细胞增殖和AOM/DSS治疗的小鼠的发生率。 SPL表达的丧失与STAT3激活的增加有关，STAT3的激活是炎症，致癌作用以及肿瘤细胞与肿瘤微环境或“利基”之间的关键调节剂。 STAT3充当许多mRNA和microRNA靶标的转录因子。 STAT3还已显示用于调节线粒体功能。重要的是，我们发现STAT3的抑制作用阻止了SPL破坏促进AOM/DSS和异种移植模型系统中肿瘤发生的能力。除了这些发现外，我们最近还确定了一个在小鼠中采用化学预防作用的大豆衍生的鞘脂家族。 SDS促进肠细胞更新，抑制STAT3，WNT和AKT信号通路，重要的是，在结肠癌细胞系中诱导SPL表达。我们的累积发现使我们提出了中心假设，该假设指出：SPL下调通过影响肠道肠菌群的肠上皮细胞和其他细胞室的STAT3依赖机制促进结肠癌发生。我们进一步提出，SD通过逆转其及其对结肠炎症和致癌作用的相关作用来作为SPL下调的解毒剂。为了检验我们的假设，我们设计了四个特定的目的：1）阐明S1P如何促进细胞转化和肿瘤发生； 2）阐明SPL在调节肿瘤生态位的作用； 3）确定SPL下调是否促进了促炎性饮食引起的肠道肿瘤发生； 4）测试SDS是否可以逆转SPL下调及其在肠道肿瘤发生过程中的相关作用。在实现这些目标时，我们应该实现两个主要目标：阐明结肠癌中SPL的生物学，并制定通过SPL重新激活而起作用的化学预防策略。