Kawamori Toshihiko, Osta Walid, Johnson Korey R, Pettus Benjamin J, Bielawski Jacek, Tanaka Takuji, Wargovich Michael J, Reddy Bandaru S, Hannun Yusuf A, Obeid Lina M, Zhou Daohong
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
FASEB J. 2006 Feb;20(2):386-8. doi: 10.1096/fj.05-4331fje. Epub 2005 Nov 30.
Sphingosine kinase 1 (SK1) phosphorylates sphingosine to form sphingosine 1-phosphate (S1P), which has the ability to promote cell proliferation and survival and stimulate angiogenesis. The SK1/S1P pathway also plays a critical role in regulation of cyclooxygenase-2 (COX-2), a well-established pathogenic factor in colon carcinogenesis. Therefore, we examined the expression of SK1 and COX-2 in rat colon tumors induced by azoxymethane (AOM) and the relationship of these two proteins in normal and malignant intestinal epithelial cells. Strongly positive SK1 staining was found in 21/28 (75%) of rat colon adenocarcinomas induced by AOM, whereas no positive SK1 staining was observed in normal mucosa. The increase in SK1 and COX-2 expression in AOM-induced rat colon adenocarcinoma was confirmed at the level of mRNA by real-time RT-PCR. In addition, it was found that 1) down-regulation of SK1 in HT-29 human colon cancer cells by small interfering RNA (siRNA) decreases COX-2 expression and PGE2 production; 2) overexpression of SK1 in RIE-1 rat intestinal epithelial cells induces COX-2 expression; and 3) S1P stimulates COX-2 expression and PGE2 production in HT-29 cells. These results suggest that the SK1/S1P pathway may play an important role in colon carcinogenesis, in part, by regulating COX-2 expression and PGE2 production.
鞘氨醇激酶1（SK1）将鞘氨醇磷酸化形成1-磷酸鞘氨醇（S1P），后者具有促进细胞增殖与存活以及刺激血管生成的能力。SK1/S1P信号通路在环氧化酶-2（COX-2）的调控中也发挥关键作用，COX-2是结肠癌发生过程中一个公认的致病因素。因此，我们检测了由氧化偶氮甲烷（AOM）诱导的大鼠结肠肿瘤中SK1和COX-2的表达，以及这两种蛋白在正常和恶性肠上皮细胞中的关系。在28例由AOM诱导的大鼠结肠腺癌中，21例（75%）呈现SK1强阳性染色，而在正常黏膜中未观察到SK1阳性染色。通过实时逆转录聚合酶链反应（RT-PCR）在mRNA水平证实了AOM诱导的大鼠结肠腺癌中SK1和COX-2表达增加。此外，还发现：1）用小干扰RNA（siRNA）下调HT-29人结肠癌细胞中的SK1可降低COX-2表达和前列腺素E2（PGE2）的产生；2）在RIE-1大鼠肠上皮细胞中过表达SK1可诱导COX-2表达；3）S1P可刺激HT-29细胞中COX-2表达和PGE2产生。这些结果表明，SK1/S1P信号通路可能在结肠癌发生过程中发挥重要作用，部分是通过调节COX-2表达和PGE2产生来实现的。
