Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer
Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer
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DOI：
10.1096/fj.201601225rr
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发表时间：
2017-09-01
期刊：
影响因子：
4.8
通讯作者：
Okazaki, Toshiro
中科院分区：
文献类型：
--
作者：
Ohnishi, Toshio;Hashizume, Chieko;Okazaki, Toshiro
鞘磷脂合成酶2（Sphingomyelin synthase 2，SMS 2）是鞘磷脂（sphingomyelin，SM）的合成酶，调节膜的流动性和微区结构。SMS2在LPS诱导的肺损伤和炎症中发挥作用;然而，其在炎症介导的肿瘤发生中的作用尚不清楚。我们研究了SMS2缺陷对葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的影响，并发现在SMS2缺陷（SMS2（-/-））小鼠中抑制DSS诱导的炎症。DSS治疗诱导神经酰胺水平显著增加，SMS2（-/-）结肠组织中SM水平降低，并证明炎症相关基因表达和促炎细胞因子和趋化因子、白细胞浸润以及MAPK和信号转导子和转录激活子3激活的升高减弱。在接受野生型骨髓移植后，SMS2（-/-）小鼠也表现出对DSS诱导的结肠炎症的抑制，这表明骨髓源性免疫细胞中的SMS2缺陷与结肠炎的抑制无关。最后，在氧化偶氮甲烷/DSS诱导的癌症模型中，SMS2缺陷显著降低了结肠中的肿瘤发病率。我们的研究结果表明，SMS2缺陷通过抑制结肠上皮细胞介导的炎症来抑制DSS诱导的结肠炎和随后的结肠炎相关结肠癌;因此，抑制SMS2可能是人类结肠炎和结直肠癌的潜在治疗靶点。
Sphingomyelin synthase 2 (SMS2) is the synthetic enzyme of sphingomyelin (SM), which regulates membrane fluidity and microdomain structure. SMS2 plays a role in LPS-induced lung injury and inflammation; however, its role in inflammation-mediated tumorigenesis is unclear. We investigated the effect of SMS2 deficiency on dextran sodium sulfate (DSS)-induced murine colitis and found inhibition of DSS-induced inflammation in SMS2-deficient (SMS2(-/-)) mice. DSS treatment induced a significant increase in ceramide levels, with a decrease of SM levels in SMS2(-/-) colon tissue, and demonstrated attenuation of the elevation of both inflammation-related gene expression and proinflammatory cytokines and chemokines, leukocyte infiltration, and MAPK and signal transducer and activator of transcription 3 activation. After undergoing transplantation of wild-type bone marrow, SMS2(-/-) mice also exhibited inhibition of DSS-induced inflammation in the colon, which suggested that SMS2 deficiency in bone marrow-derived immune cells was not involved in the inhibition of colitis. Finally, in an azoxymethane/DSS-induced cancer model, SMS2 deficiency significantly decreased tumor incidence in the colon. Our results demonstrate that SMS2 deficiency inhibits DSS-induced colitis and subsequent colitis-associated colon cancer via inhibition of colon epithelial cell-mediated inflammation; therefore, inhibition of SMS2 may be a potential therapeutic target for human colitis and colorectal cancer.