Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlandia, Umuarama, Uberlandia, MG 38400-902, Brazil
Obstetric Division, Internal Medicine, University Hospital, Federal University of Uberlandia, Umuarama, Uberlandia, MG 38405-320, Brazil
Int J Mol Sci. 2017 Nov 24;18(12):2521. doi: 10.3390/ijms18122521.
Sphingolipid metabolism pathway is essential in membrane homeostasis, and its dysfunction has been associated with favorable tumor microenvironment, disease progression, and chemotherapy resistance. Its major components have key functions on survival and proliferation, with opposing effects. We have profiled the components of the sphingolipid pathway on leukocytes of breast cancer (BC) patients undergoing chemotherapy treatment and without, including the five sphingosine 1-phosphate (S1P) receptors, the major functional genes, and cytokines, in order to better understand the S1P signaling in the immune cells of these patients. To the best of our knowledge, this is the first characterization of the sphingolipid pathway in whole blood of BC patients. Skewed gene profiles favoring high expression toward S1P production during BC development was observed, which was reversed by chemotherapy treatment, and reached similar levels to those found in healthy donors. Such levels were also correlated with high levels of TNF-α. Our data revealed an important role of the sphingolipid pathway in immune cells in BC with skewed signaling of S1P receptors, which favored cancer development even under chemotherapy, and may probably be a trigger of cancer resistance. Thus, these molecules must be considered as a target pathway for combined BC therapeutics.
鞘脂代谢途径对于膜内稳态至关重要，其功能障碍与有利的肿瘤微环境、疾病进展和化疗耐药性有关。其主要成分在存活和增殖方面具有关键作用，具有相反的效果。我们对正在接受化疗和未接受化疗的乳腺癌（BC）患者的白细胞中的鞘脂途径的成分进行了分析，包括 5 种鞘氨醇 1-磷酸（S1P）受体、主要功能基因和细胞因子，以便更好地了解这些患者免疫细胞中的 S1P 信号。据我们所知，这是首次对 BC 患者全血中的鞘脂途径进行特征描述。在 BC 发展过程中，观察到有利于 S1P 产生的偏向性基因谱，这种情况在化疗治疗后得到逆转，并达到与健康供体相似的水平。这些水平也与 TNF-α 的高水平相关。我们的数据揭示了鞘脂途径在 BC 免疫细胞中的重要作用，S1P 受体的信号传导出现偏差，即使在化疗下也有利于癌症的发展，并且可能是癌症耐药性的触发因素。因此，这些分子必须被视为联合治疗 BC 的靶向途径。
