Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis.
Generation of sphingosine-1-phosphate is enhanced in biliary tract cancer patients and is associated with lymphatic metastasis.
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DOI：
10.1038/s41598-018-29144-9
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发表时间：
2018-07-17
影响因子：
4.6
通讯作者：
Wakai T
中科院分区：
文献类型：
--
作者：
Hirose Y;Nagahashi M;Katsuta E;Yuza K;Miura K;Sakata J;Kobayashi T;Ichikawa H;Shimada Y;Kameyama H;McDonald KA;Takabe K;Wakai T
已知淋巴转移会导致胆道癌（BTC）预后更差。最近，鞘氨醇 - 1 - 磷酸（S1P）这种由鞘氨醇激酶1（SPHK1）产生的生物活性脂质介质，已被证实在多种癌症的淋巴管生成和淋巴结转移中发挥重要作用。然而，这种脂质介质在胆道癌中的作用从未被研究过。在此我们发现，随着神经酰胺合成途径的激活，S1P在胆道癌中升高，这表明胆道癌利用SPHK1促进淋巴转移。我们通过液相色谱 - 电喷雾电离 - 串联质谱（LC - ESI - MS/MS）发现，与正常胆道组织相比，S1P、鞘氨醇以及神经酰胺前体（如单己糖基神经酰胺和鞘磷脂）在胆道癌中显著增加，但神经酰胺没有增加。利用癌症基因组图谱队列，我们证明了胆道癌中的S1P是通过从头合成途径产生，并通过ABCC1转运出去的。此外，我们发现SPHK1的表达与胆道癌中与淋巴转移相关的因素呈正相关。最后，免疫组化检测显示，有淋巴结转移的胆囊癌中磷酸化 - SPHK1的表达明显高于无淋巴结转移的胆囊癌。综上所述，我们的数据表明，胆道癌中产生的S1P有助于淋巴转移。
Lymphatic metastasis is known to contribute to worse prognosis of biliary tract cancer (BTC). Recently, sphingosine-1-phosphate (S1P), a bioactive lipid mediator generated by sphingosine kinase 1 (SPHK1), has been shown to play an important role in lymphangiogenesis and lymph node metastasis in several types of cancer. However, the role of the lipid mediator in BTC has never been examined. Here we found that S1P is elevated in BTC with the activation of ceramide-synthetic pathways, suggesting that BTC utilizes SPHK1 to promote lymphatic metastasis. We found that S1P, sphingosine and ceramide precursors such as monohexosyl-ceramide and sphingomyelin, but not ceramide, were significantly increased in BTC compared to normal biliary tract tissue using LC-ESI-MS/MS. Utilizing The Cancer Genome Atlas cohort, we demonstrated that S1P in BTC is generated via de novo pathway and exported via ABCC1. Further, we found that SPHK1 expression positively correlated with factors related to lymphatic metastasis in BTC. Finally, immunohistochemical examination revealed that gallbladder cancer with lymph node metastasis had significantly higher expression of phospho-SPHK1 than that without. Taken together, our data suggest that S1P generated in BTC contributes to lymphatic metastasis.
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