Increased mRNA Levels of Sphingosine Kinases and S1P Lyase and Reduced Levels of S1P Were Observed in Hepatocellular Carcinoma in Association with Poorer Differentiation and Earlier Recurrence.
Increased mRNA Levels of Sphingosine Kinases and S1P Lyase and Reduced Levels of S1P Were Observed in Hepatocellular Carcinoma in Association with Poorer Differentiation and Earlier Recurrence.
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DOI：
10.1371/journal.pone.0149462
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Yatomi Y
中科院分区：
文献类型：
--
作者：
Uranbileg B;Ikeda H;Kurano M;Enooku K;Sato M;Saigusa D;Aoki J;Ishizawa T;Hasegawa K;Kokudo N;Yatomi Y
尽管据报道 1-磷酸鞘氨醇 (S1P) 在癌症病理生理学中发挥重要作用，但人们对 S1P 和肝细胞癌 (HCC) 知之甚少。为了阐明S1P与HCC之间的关系，本研究连续纳入77例接受手术治疗的HCC患者。此外，S1P 及其代谢物通过 LC-MS/MS 进行定量。与邻近的非 HCC 组织相比，HCC 组织中鞘氨醇激酶 (SK) 的 mRNA 水平升高，SKs 可磷酸化鞘氨醇生成 S1P。 HCC 中较高的 SKs mRNA 水平与较差的分化和微血管侵袭相关，而较高水平的 SK2 mRNA 是肝内和肝外复发的危险因素。然而，与非 HCC 组织相比，HCC 中的 S1P 水平出乎意料地降低，并且与非 HCC 组织相比，在 HCC 中观察到降解 S1P 的 S1P 裂解酶 (SPL) 的 mRNA 水平增加。 HCC 中较高的 SPL mRNA 水平与较差的分化相关。最后，在 HCC 细胞系中，siRNA 抑制 SK 或 SPL 的表达导致增殖、侵袭和迁移减少，而 SK 或 SPL 的过度表达则增强增殖。总之，与邻近的非 HCC 组织相比，HCC 组织中 SK 和 SPL mRNA 表达增加以及 S1P 水平降低更常见，并且与分化不良和早期复发相关。 SPL 和 SK 可能是 HCC 治疗的治疗靶点。
Although sphingosine 1-phosphate (S1P) has been reported to play an important role in cancer pathophysiology, little is known about S1P and hepatocellular carcinoma (HCC). To clarify the relationship between S1P and HCC, 77 patients with HCC who underwent surgical treatment were consecutively enrolled in this study. In addition, S1P and its metabolites were quantitated by LC-MS/MS. The mRNA levels of sphingosine kinases (SKs), which phosphorylate sphingosine to generate S1P, were increased in HCC tissues compared with adjacent non-HCC tissues. Higher mRNA levels of SKs in HCC were associated with poorer differentiation and microvascular invasion, whereas a higher level of SK2 mRNA was a risk factor for intra- and extra-hepatic recurrence. S1P levels, however, were unexpectedly reduced in HCC compared with non-HCC tissues, and increased mRNA levels of S1P lyase (SPL), which degrades S1P, were observed in HCC compared with non-HCC tissues. Higher SPL mRNA levels in HCC were associated with poorer differentiation. Finally, in HCC cell lines, inhibition of the expression of SKs or SPL by siRNA led to reduced proliferation, invasion and migration, whereas overexpression of SKs or SPL enhanced proliferation. In conclusion, increased SK and SPL mRNA expression along with reduced S1P levels were more commonly observed in HCC tissues compared with adjacent non-HCC tissues and were associated with poor differentiation and early recurrence. SPL as well as SKs may be therapeutic targets for HCC treatment.