Aquaporin-7 Regulates the Response to Cellular Stress in Breast Cancer.
Aquaporin-7 Regulates the Response to Cellular Stress in Breast Cancer.
复制标题
水通道蛋白-7调节乳腺癌细胞应激反应。
DOI：
10.1158/0008-5472.can-19-2269
复制
发表时间：
2020-10-01
期刊：
影响因子：
11.2
通讯作者：
Littlepage LE
中科院分区：
文献类型：
--
作者：
Dai C;Charlestin V;Wang M;Walker ZT;Miranda-Vergara MC;Facchine BA;Wu J;Kaliney WJ;Dovichi NJ;Li J;Littlepage LE
癌症代谢、基因表达和致癌驱动基因之间复杂而又相互关联的联系有可能识别具有预后和治疗价值的新的生物标记物和药物靶点。在这里，我们通过一种新的基于无偏相关性的网络分析，有效地整合了乳腺癌小鼠模型的代谢组学和基因表达数据。该方法确定了35个代谢物和34个基因枢纽具有最大的网络相关性。这些中枢具有预后价值，可能是肿瘤代谢和乳腺癌不可或缺的一部分。水和甘油通道基因Hub Aquaporin-7(Aqp7)被认为是乳腺癌的一种新的调节因子。AQP7是预测乳腺癌患者总生存期的指标。在小鼠乳腺癌模型中，Aqp7表达减少导致原发肿瘤负担和肺转移减少。Aqp7降低的细胞和肿瘤的代谢组学和复杂的脂谱显示，与对照组相比，脂代谢、谷胱甘肽代谢和尿素/精氨酸代谢显著改变。这些数据确定AQP7是乳腺癌对环境细胞压力的代谢和信号反应的关键调节因子，突出表明AQP7是一种潜在的癌症特异性治疗脆弱性。
The complex yet interrelated connections between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. Here we effectively integrated metabolomics and gene expression data from breast cancer mouse models through a novel unbiased correlation-based network analysis. This approach identified 35 metabolite and 34 gene hubs with the most network correlations. These hubs have prognostic value and are likely integral to tumor metabolism and breast cancer. The gene hub Aquaporin-7 (Aqp7), a water and glycerol channel, was identified as a novel regulator of breast cancer. AQP7 was prognostic of overall survival in breast cancer patients. In mouse breast cancer models, reduced expression of Aqp7 caused reduced primary tumor burden and lung metastasis. Metabolomics and complex lipid profiling of cells and tumors with reduced Aqp7 revealed significantly altered lipid metabolism, glutathione metabolism, and urea/arginine metabolism compared to controls. These data identify AQP7 as a critical regulator of metabolic and signaling responses to environmental cellular stresses in breast cancer, highlighting AQP7 as a potential cancer-specific therapeutic vulnerability.