Different Roles of Sphingosine Kinase 1 and 2 in Pancreatic Cancer Progression
Different Roles of Sphingosine Kinase 1 and 2 in Pancreatic Cancer Progression
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DOI：
10.1016/j.jss.2018.06.019
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发表时间：
2018-12-01
影响因子：
2.2
通讯作者：
Wakai, Toshifumi
中科院分区：
文献类型：
--
作者：
Yuza, Kizuki;Nakajima, Masato;Wakai, Toshifumi
背景：胰腺癌是一种预后不良的疾病，开发新的治疗方法是必要的。鞘氨醇-1-磷酸（S1 P）是由鞘氨醇激酶（SphK 1和SphK 2）产生的生物活性脂质介质，在许多类型的癌症进展中起关键作用。然而，对鞘氨醇激酶在胰腺癌中的作用知之甚少。本研究旨在探讨鞘氨醇激酶在胰腺癌发生发展中的作用。材料与方法：检测10例胰腺癌及癌旁胰腺组织中S1 P的含量。我们产生了具有成簇规则间隔短回文重复序列（CRISPR）/CRISPR相关系统基因9（Cas9）介导的SphK 1或SphK 2缺失的PAN 02鼠胰腺癌细胞系，并评估了细胞生长和迁移。结果：胰腺癌组织中S1 P水平显著高于癌旁组织，胰腺癌组织中S1 P水平显著高于癌旁组织。SphK 1敲除（KO）细胞显示出比野生型（WT）细胞更大的增殖和迁移，SphK 2 KO细胞显示出比WT细胞更少的增殖和迁移。动物实验显示，注射SphK 1 KO细胞的小鼠存活时间明显短于注射WT细胞的小鼠，注射SphK 2 KO细胞的小鼠存活时间长于注射WT细胞的小鼠。结论：SphK 1和SphK 2产生的S1 P在胰腺癌细胞中可能具有不同的功能。靶向SphK 1和SphK 2可能是胰腺癌治疗的潜在策略。(C)2018爱思唯尔公司All rights reserved.
Background: Pancreatic cancer is a disease with poor prognosis, and development of new treatments is necessary. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by sphingosine kinases (SphK1 and SphK2), plays a critical role in progression of many types of cancer. However, little is known about the role of sphingosine kinases in pancreatic cancer. This study investigated the roles of sphingosine kinases in pancreatic cancer progression.Materials and methods: S1P levels in pancreatic cancer and noncancerous pancreatic tissue were measured in 10 patients. We generated PAN02 murine pancreatic cancer cell lines with a clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated system genes 9 (Cas9)-mediated deletion of SphK1 or SphK2 and assessed cell growth and migration. In an animal model, we assessed the survival of mice injected with PAN02 cells intraperitoneally.Results: S1P levels in the pancreatic cancer tissue were significantly higher than those in noncancerous tissue. SphK1 knockout (KO) cells showed greater proliferation and migration than wild type (WT) cells, and SphK2 KO cells showed less proliferation and migration than WT cells. Animal experiments showed that the survival of mice injected with SphK1 KO cells was significantly shorter than those injected with WT cells, and the survival of mice injected with SphK2 KO cells was longer than those injected with WT cells. Surprisingly, cytotoxic assay using gemcitabine showed that SphK1 KO cells survived less than WT cells, and SphK2 KO cells survived more than WT cells.Conclusions: S1P produced by SphK1 and SphK2 may have different functions in pancreatic cancer cells. Targeting both SphK1 and SphK2 may be a potential strategy for pancreatic cancer treatment. (C) 2018 Elsevier Inc. All rights reserved.