Sphingosine kinase 1 is required for TGF-β mediated fibroblastto- myofibroblast differentiation in ovarian cancer.
Sphingosine kinase 1 is required for TGF-β mediated fibroblastto- myofibroblast differentiation in ovarian cancer.
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DOI：
10.18632/oncotarget.6703
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发表时间：
2016-01-26
期刊：
影响因子：
--
通讯作者：
Orsulic S
中科院分区：
文献类型：
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作者：
Beach JA;Aspuria PJ;Cheon DJ;Lawrenson K;Agadjanian H;Walsh CS;Karlan BY;Orsulic S
鞘氨醇激酶1（SPHK1），产生鞘氨醇1磷酸（S1P）的酶，已知在许多癌症中高度表达。然而，SPHK 1在肿瘤间质细胞中的作用仍不清楚。在这里，我们发现SPHK1在高级别浆液性卵巢癌（HGSC）的肿瘤间质中高度表达，并且是癌症相关成纤维细胞（CAFs）的分化和肿瘤促进功能所必需的。卵巢成纤维细胞中SPHK1的敲除或药物抑制减弱了TGF-β诱导的CAF标记物的表达，并降低了它们在共培养系统中促进卵巢癌细胞迁移和侵袭的能力。从机制上讲，我们确定SPHK1通过S1P受体（S1PR2和S1PR3）的反式激活介导TGF-β信号传导，导致p38 MAPK磷酸化。基质SPHK1在肿瘤发生中的重要性在体内得到证实，通过证明SPHK1敲除小鼠中肿瘤生长和转移的显著减少。总的来说，这些发现证明了SPHK1抑制作为HGSC中新型基质靶向治疗的潜力。
Sphingosine kinase 1 (SPHK1), the enzyme that produces sphingosine 1 phosphate (S1P), is known to be highly expressed in many cancers. However, the role of SPHK1 in cells of the tumor stroma remains unclear. Here, we show that SPHK1 is highly expressed in the tumor stroma of high-grade serous ovarian cancer (HGSC), and is required for the differentiation and tumor promoting function of cancer-associated fibroblasts (CAFs). Knockout or pharmacological inhibition of SPHK1 in ovarian fibroblasts attenuated TGF-β-induced expression of CAF markers, and reduced their ability to promote ovarian cancer cell migration and invasion in a coculture system. Mechanistically, we determined that SPHK1 mediates TGF-β signaling via the transactivation of S1P receptors (S1PR2 and S1PR3), leading to p38 MAPK phosphorylation. The importance of stromal SPHK1 in tumorigenesis was confirmed in vivo, by demonstrating a significant reduction of tumor growth and metastasis in SPHK1 knockout mice. Collectively, these findings demonstrate the potential of SPHK1 inhibition as a novel stroma-targeted therapy in HGSC.