Kang June Hee, Kim Hyun Ji, Park Mi Kyung, Lee Chang Hoon
College of Pharmacy, Dongguk University, Seoul 10326, Republic of Korea.
National Cancer Center, Goyang, 10408, Republic of Korea.
Biomol Ther (Seoul). 2017 Nov 1;25(6):625-633. doi: 10.4062/biomolther.2016.228.
Sphingosylphosphorylcholine (SPC) is one of the bioactive phospholipids that has many cellular functions such as cell migration, adhesion, proliferation, angiogenesis, and Ca²⁺ signaling. Recent studies have reported that SPC induces invasion of breast cancer cells via matrix metalloproteinase-3 (MMP-3) secretion leading to WNT activation. Thrombospondin-1 (TSP-1) is a matricellular and calcium-binding protein that binds to a wide variety of integrin and non-integrin cell surface receptors. It regulates cell proliferation, migration, and apoptosis in inflammation, angiogenesis and neoplasia. TSP-1 promotes aggressive phenotype via epithelial mesenchymal transition (EMT). The relationship between SPC and TSP-1 is unclear. We found SPC induced EMT leading to mesenchymal morphology, decrease of E-cadherin expression and increases of N-cadherin and vimentin. SPC induced secretion of thrombospondin-1 (TSP-1) during SPC-induced EMT of various breast cancer cells. Gene silencing of TSP-1 suppressed SPC-induced EMT as well as migration and invasion of MCF10A cells. An extracellular signal-regulated kinase inhibitor, PD98059, significantly suppressed the secretion of TSP-1, expressions of N-cadherin and vimentin, and decrease of E-cadherin in MCF10A cells. ERK2 siRNA suppressed TSP-1 secretion and EMT. From online PROGgene V2, relapse free survival is low in patients having high TSP-1 expressed breast cancer. Taken together, we found that SPC induced EMT and TSP-1 secretion via ERK2 signaling pathway. These results suggests that SPC-induced TSP-1 might be a new target for suppression of metastasis of breast cancer cells.
鞘氨醇磷酸胆碱（SPC）是一种具有多种细胞功能的生物活性磷脂，如细胞迁移、黏附、增殖、血管生成和Ca²⁺信号传导。最近的研究报道，SPC通过基质金属蛋白酶-3（MMP-3）分泌诱导乳腺癌细胞侵袭，导致WNT激活。血小板反应蛋白-1（TSP-1）是一种基质细胞蛋白和钙结合蛋白，可与多种整合素和非整合素细胞表面受体结合。它在炎症、血管生成和肿瘤形成过程中调节细胞增殖、迁移和凋亡。TSP-1通过上皮-间质转化（EMT）促进侵袭性表型。SPC与TSP-1之间的关系尚不清楚。我们发现SPC诱导EMT，导致间充质形态、E-钙黏蛋白表达降低以及N-钙黏蛋白和波形蛋白增加。在各种乳腺癌细胞的SPC诱导的EMT过程中，SPC诱导血小板反应蛋白-1（TSP-1）的分泌。TSP-1基因沉默抑制了SPC诱导的EMT以及MCF10A细胞的迁移和侵袭。一种细胞外信号调节激酶抑制剂PD98059显著抑制了MCF10A细胞中TSP-1的分泌、N-钙黏蛋白和波形蛋白的表达以及E-钙黏蛋白的降低。ERK2 siRNA抑制TSP-1分泌和EMT。从在线PROGgene V2数据库可知，TSP-1高表达的乳腺癌患者无复发生存率较低。综上所述，我们发现SPC通过ERK2信号通路诱导EMT和TSP-1分泌。这些结果表明，SPC诱导的TSP-1可能是抑制乳腺癌细胞转移的新靶点。
