Role for sphingosine kinase 1 in colon carcinogenesis
Role for sphingosine kinase 1 in colon carcinogenesis
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DOI：
10.1096/fj.08-117572
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发表时间：
2009-02-01
期刊：
影响因子：
4.8
通讯作者：
Obeid, Lina M.
中科院分区：
文献类型：
--
作者：
Kawamori, Toshihiko;Kaneshiro, Tatsuya;Obeid, Lina M.
鞘氨醇激酶1（SphK 1）磷酸化鞘氨醇以形成鞘氨醇-1-磷酸（S1 P），并且是鞘脂介导的功能的关键调节剂。基于细胞的研究表明SphK 1/S1 P通路具有促肿瘤功能。此外，我们以前的研究暗示SphK 1/S1 P通路诱导花生四烯酸级联反应，一个主要的炎症途径参与结肠癌的发生。因此，我们研究了SphK 1/S1 P通路是否是介导体内致癌所必需的。在这里，我们报告说，89%（42/47）的人结肠癌样本SphK 1染色阳性，而正常结肠粘膜有阴性或弱染色。结肠腺瘤中SphK 1的表达高于正常粘膜，结肠癌中有转移者SphK 1的表达高于无转移者。在氧化偶氮甲烷（AOM）小鼠结肠癌模型中，与正常粘膜相比，SphK 1和S1 P在结肠癌组织中显著升高。此外，患有结肠癌的小鼠的S1 P血液水平高于没有癌症的小鼠。值得注意的是，经受AOM的SphK 1（-/-）小鼠具有显著更少的异常隐窝病灶（ACF）形成，并且显著减少结肠癌的发展。这些结果是第一个体内证据表明，SphK 1/S1 P途径有助于结肠癌的发生，抑制这一途径是化学预防的潜在目标。- Kawamori，T.，Kaneshiro，T.，Okumura，M.，Maalouf，S.，Uflacker，A.，Bielawski，J.，Hannun，Y.一、奥贝德湖M.鞘氨醇激酶1在结肠癌发生中的作用。FASEB J. 23，405-414（2009）
Sphingosine kinase 1 (SphK1) phosphorylates sphingosine to form sphingosine-1-phosphate (S1P) and is a critical regulator of sphingolipid-mediated functions. Cell-based studies suggest a tumor-promoting function for the SphK1/S1P pathway. Also, our previous studies implicated the SphK1/S1P pathway in the induction of the arachidonic acid cascade, a major inflammatory pathway involved in colon carcinogenesis. Therefore, we investigated whether the SphK1/S1P pathway is necessary for mediating carcinogenesis in vivo. Here, we report that 89% (42/47) of human colon cancer samples stained positively for SphK1, whereas normal colon mucosa had negative or weak staining. Adenomas had higher expression of SphK1 vs. normal mucosa, and colon cancers with metastasis had higher expression of SphK1 than those without metastasis. In the azoxymethane (AOM) murine model of colon cancer, SphK1 and S1P were significantly elevated in colon cancer tissues compared to normal mucosa. Moreover, blood levels of S1P were higher in mice with colon cancers than in those without cancers. Notably, SphK1(-/-) mice subjected to AOM had significantly less aberrant crypt foci (ACF) formation and significantly reduced colon cancer development. These results are the first in vivo evidence that the SphK1/S1P pathway contributes to colon carcinogenesis and that inhibition of this pathway is a potential target for chemoprevention. - Kawamori, T., Kaneshiro, T., Okumura, M., Maalouf, S., Uflacker, A., Bielawski, J., Hannun, Y. A., Obeid, L. M. Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 23, 405-414 (2009)