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）：膳食鞘脂，例如鞘氨醇和神经酰胺，可促进肠上皮细胞的更新，并已被证明可以防止小鼠肠道肿瘤的发生。然而，肠上皮细胞吸收的鞘氨醇可被致癌酶 SphK1 磷酸化，生成 1-磷酸鞘氨醇 (S1P)，这是一种有丝分裂脂质，可抑制细胞凋亡并促进炎症、转化和癌变。因此，饮食中的鞘脂对于结肠癌来说是一把双刃剑。阐明它们在致癌过程中的具体作用是开发基于鞘脂的策略来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，该酶在肠细胞和肠粘膜的其他细胞区室中高度表达。我们之前表明，SPL 在 ApcMin/+ 小鼠腺瘤和人类结肠癌中下调。我们现在发现，在氧化偶氮甲烷/葡聚糖硫酸钠 (AOM/DSS) 治疗的小鼠肿瘤中，SPL 也被下调。因此，SPL下调是肠道肿瘤的一个共同特征。我们生成了肠道特异性 SPL 敲除小鼠 (SPLGutKO)，并证明肠上皮细胞 SPL 表达缺失会促进 ApcMin/+ 小鼠的肿瘤发生，并增强 AOM/DSS 治疗小鼠的结肠炎、肠上皮细胞增殖和肿瘤发生率。 SPL 表达的丧失与 STAT3 的激活增加有关，STAT3 是炎症、癌变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 作为转录因子，具有许多 mRNA 和 microRNA 靶标。 STAT3 也被证明可以调节线粒体功能。重要的是，我们发现抑制 STAT3 可以阻止 SPL 破坏促进 AOM/DSS 和异种移植模型系统中肿瘤发生的能力。除了这些发现之外，我们最近还发现了一个大豆衍生鞘脂家族，称为鞘二烯 (SD)，对小鼠具有化学预防作用。 SD 促进肠上皮细胞更新，抑制 STAT3、WNT 和 AKT 信号通路，更重要的是，诱导结肠癌细胞系中的 SPL 表达。我们的累积发现使我们提出了我们的中心假设，该假设指出：SPL 下调通过影响肠上皮细胞和肿瘤生态位的其他细胞区室的 STAT3 依赖性机制促进结肠癌发生。我们进一步提出，SDs 通过逆转 SPL 下调及其对结肠炎症和癌变的相关影响，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目标：1）阐明S1P如何促进细胞转化和肿瘤发生； 2）阐明SPL在调节肿瘤微环境中的作用； 3) 确定SPL下调是否会促进促炎饮食诱导的肠道肿瘤发生； 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影响。在实现这些目标的过程中，我们应该实现两个主要目标：阐明 SPL 在结肠癌中的生物学作用，并制定通过重新激活 SPL 发挥作用的化学预防策略。