Ceramide species are elevated in human breast cancer and are associated with less aggressiveness.
Ceramide species are elevated in human breast cancer and are associated with less aggressiveness.
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DOI：
10.18632/oncotarget.24903
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发表时间：
2018-04-13
期刊：
影响因子：
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通讯作者：
Nagahashi M
中科院分区：
文献类型：
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作者：
Moro K;Kawaguchi T;Tsuchida J;Gabriel E;Qi Q;Yan L;Wakai T;Takabe K;Nagahashi M
鞘脂已成为癌细胞存活和死亡的关键调节分子。尽管在实验模型中已经报道了鞘脂在乳腺癌进展中的重要作用，但它们在人类患者中的作用尚未被揭示。本研究的目的是探讨神经酰胺水平及其生物合成途径在人类乳腺癌患者。从44名乳腺癌患者的手术标本中收集乳腺癌、肿瘤周围和正常乳腺组织样品。通过质谱法测定组织中鞘脂代谢物的量。癌症基因组图谱用于分析与鞘脂代谢相关的基因表达。与正常和肿瘤周围乳腺组织相比，乳腺癌组织中的神经酰胺水平更高。在癌症中，生成神经酰胺的底物和酶在所有三种神经酰胺生物合成途径中显著增加。此外，乳腺癌中较高水平的神经酰胺与由Ki-67指数和癌症的核分级呈现的较低侵袭性癌症生物学相关。有趣的是，三种主要神经酰胺合成途径中酶基因表达较高的患者预后明显较差。这是第一项揭示乳腺癌患者神经酰胺代谢临床相关性的研究。我们证明，在乳腺癌组织中的神经酰胺水平显着高于正常组织中，与激活的三个神经酰胺生物合成途径。我们还发现，神经酰胺水平与侵袭性表型有显着相关性，其酶对乳腺癌患者的预后有影响。
Sphingolipids have emerged as key regulatory molecules in cancer cell survival and death. Although important roles of sphingolipids in breast cancer progression have been reported in experimental models, their roles in human patients are yet to be revealed. The aim of this study was to investigate the ceramide levels and its biosynthesis pathways in human breast cancer patients. Breast cancer, peri-tumor and normal breast tissue samples were collected from surgical specimens from a series of 44 patients with breast cancer. The amount of sphingolipid metabolites in the tissue were determined by mass spectrometry. The Cancer Genome Atlas was used to analyze gene expression related to the sphingolipid metabolism. Ceramide levels were higher in breast cancer tissue compared to both normal and peri-tumor breast tissue. Substrates and enzymes that generate ceramide were significantly increased in all three ceramide biosynthesis pathways in cancer. Further, higher levels of ceramide in breast cancer were associated with less aggressive cancer biology presented by Ki-67 index and nuclear grade of the cancer. Interestingly, patients with higher gene expressions of enzymes in the three major ceramide synthesis pathways showed significantly worse prognosis. This is the first study to reveal the clinical relevance of ceramide metabolism in breast cancer patients. We demonstrated that ceramide levels in breast cancer tissue were significantly higher than those in normal tissue, with activation of the three ceramide biosynthesis pathways. We also identified that ceramide levels have a significant association with aggressive phenotype and its enzymes have prognostic impact on breast cancer patients.