Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs
Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs
复制标题
DOI：
10.1172/jci74188
复制
发表时间：
2014-12-01
影响因子：
15.9
通讯作者：
Saba, Julie D.
中科院分区：
文献类型：
--
作者：
Begagne, Emilie;Pandurangan, Ashok;Saba, Julie D.
越来越多的证据支持炎症和癌症之间的联系;然而，炎症和癌变之间的过渡介质仍然不完全清楚。鞘氨醇-1-磷酸（Sip）裂解酶（SPL）不可逆地降解生物活性鞘脂SW，并在肠细胞中高度表达，但在结肠癌中下调。在这里，我们研究了SPL在结肠炎相关癌症（CAC）中的作用。我们产生了肠上皮特异性Sgpl 1缺失的小鼠，并在这些动物中化学诱导结肠炎和肿瘤形成。与对照动物相比，缺乏肠SPL的小鼠表现出更大的疾病活动性、结肠缩短、细胞因子水平、S1 P积累、肿瘤、STAT 3活化、STAT 3活化的microRNA（miRNAs）和miR靶向抗癌基因产物的抑制。这种表型通过STAT 3抑制而减弱。在成纤维细胞中，沉默SPL通过一种途径促进致瘤性转化，该途径涉及S1 P通过S1 P转运蛋白spinster同系物2（SPNS 2）的细胞外转运、S1 P受体激活、JAK 2/STAT 3依赖性miR-181 b-1诱导和miR-181 b-1靶向圆柱瘤病（CYLD）的沉默。炎症性肠病患者的结肠活检显示SW和STAT 3信号增强。在患有化学诱导CAC的小鼠中，口服植物型鞘脂（称为sphingadienes）增加了结肠SPL水平，降低了SW水平，STAT 3信号传导，细胞因子水平和肿瘤发生，表明SPL可防止转化和致癌。总之，我们的研究结果表明，膳食鞘脂可以增加或预防结肠癌，这取决于它们是否代谢为SW或通过SPL的作用促进S1 P代谢。
Growing evidence supports a link between inflammation and cancer; however, mediators of the transition between inflammation and carcinogenesis remain incompletely understood. Sphingosine-1-phosphate (Sip) lyase (SPL) irreversibly degrades the bioactive sphingolipid SW and is highly expressed in enterocytes but downregulated in colon cancer. Here, we investigated the role of SPL in colitis-associated cancer (CAC). We generated mice with intestinal epithelium-specific Sgpl1 deletion and chemically induced colitis and tumor formation in these animals. Compared with control animals, mice lacking intestinal SPL exhibited greater disease activity, colon shortening, cytokine levels, S1P accumulation, tumors, STAT3 activation, STAT3-activated microRNAs (miRNAs), and suppression of miR-targeted anti-oncogene products. This phenotype was attenuated by STAT3 inhibition. In fibroblasts, silencing SPL promoted tumorigenic transformation through a pathway involving extracellular transport of S1P through S1P transporter spinster homolog 2 (SPNS2), S1P receptor activation, JAK2/STAT3-dependent miR-181b-1 induction, and silencing of miR-181b-1 target cylindromatosis (CYLD). Colon biopsies from patients with inflammatory bowel disease revealed enhanced SW and STAT3 signaling. In mice with chemical-induced CAC, oral administration of plant-type sphingolipids called sphingadienes increased colonic SPL levels and reduced SW levels, STAT3 signaling, cytokine levels, and tumorigenesis, indicating that SPL prevents transformation and carcinogenesis. Together, our results suggest that dietary sphingolipids can augment or prevent colon cancer, depending upon whether they are metabolized to SW or promote S1P metabolism through the actions of SPL.