S1P lyase in colon cancer

描述（由申请人提供）：膳食鞘脂如鞘氨醇和神经酰胺促进肠细胞更新，并已被证明可以防止小鼠肠道肿瘤的发生。然而，肠细胞摄取的鞘氨醇可被致癌酶SphK1磷酸化，生成鞘氨醇-1-磷酸（S1P），这是一种抑制细胞凋亡、促进炎症、转化和致癌的有丝分裂性脂质。因此，饮食鞘脂在结肠癌中是一把双刃剑。阐明它们在癌变中的具体作用是开发以鞘脂为基础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，该酶在肠细胞和肠粘膜的其他细胞区室中高度表达。我们之前的研究表明，SPL在ApcMin/+小鼠腺瘤和人类结肠癌中下调。我们现在发现，在偶氮氧甲烷/葡聚糖硫酸钠（AOM/DSS）处理的小鼠中，SPL在肿瘤中也下调。因此，SPL下调是肠道肿瘤的共同特征。我们构建了肠道特异性SPL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处理小鼠的结肠炎、肠细胞增殖和肿瘤发生率。SPL表达的缺失与STAT3激活的增加有关，STAT3是炎症、致癌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，具有许多mRNA和microRNA靶点。STAT3也被证明可以调节线粒体功能。重要的是，我们发现STAT3的抑制阻止了在AOM/DSS和异种移植模型系统中SPL破坏促进肿瘤发生的能力。除了这些发现之外，我们最近还发现了一个大豆衍生的鞘脂家族，称为鞘脂二烯（SDs），在小鼠中具有化学预防作用。SDs促进肠细胞更新，抑制STAT3、WNT和AKT信号通路，重要的是，诱导结肠癌细胞系中SPL的表达。我们的累积发现使我们提出了我们的中心假设，即：SPL下调通过stat3依赖机制促进结肠癌的发生，这种机制影响肠上皮细胞和肿瘤生态位的其他细胞区室。我们进一步提出，SDs通过逆转SPL下调及其对结肠炎症和致癌的相关作用，可以作为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在调节肿瘤生态位中的作用；3)探讨促炎饮食诱导的SPL下调是否促进肠道肿瘤发生；4)检测SDs是否能逆转肠道肿瘤发生过程中SPL下调及其相关作用。为了实现这些目标，我们应该实现我们的两个主要目标：阐明结肠癌中SPL的生物学特性，并开发通过SPL再激活起作用的化学预防策略。

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.