NDRG1 regulates neutral lipid metabolism in breast cancer cells.
NDRG1 regulates neutral lipid metabolism in breast cancer cells.
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DOI：
10.1186/s13058-018-0980-4
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发表时间：
2018-06-14
期刊：
影响因子：
--
通讯作者：
Conklin DS
中科院分区：
文献类型：
--
作者：
Sevinsky CJ;Khan F;Kokabee L;Darehshouri A;Maddipati KR;Conklin DS
脂质代谢改变是侵袭性乳腺癌的一个新标志。 N-myc 下游调节基因 (NDRG1) 基因在周围神经系统髓鞘形成中发挥着关键作用，因为失活突变会导致严重的脱髓鞘神经病。在乳腺癌中，NDRG1 表达升高与临床结果相关，但其在乳腺癌生理学中的功能作用仍不清楚。对多个大型公开基因组数据库中的 NDRG1 表达进行了荟萃分析。评估了全基因组表达相关性、Cox 比例风险以及与表达升高相关的临床结果的 Kaplan-Meier 模型。为了研究 NDRG1 功能，在代表所有主要乳腺癌分子亚型的一组细胞系中进行了基因沉默和过度表达表型研究。通过高通量定量显微镜评估由于 NDRG1 表达改变导致的细胞增殖、形态和中性脂质积累的变化。应用综合脂质组学质谱分析来表征由于 NDRG1 沉默导致的脂质种类的整体变化。标记的脂肪酸用于监测营养充足和饥饿培养条件下细胞脂肪酸的摄取和亚细胞分布。 NDRG1 过度表达与糖酵解和缺氧相关基因表达相关，并与转移率和患者死亡率升高相关。沉默 NDRG1 会降低细胞增殖率，导致脂质代谢功能障碍，包括增加脂肪酸掺入中性脂质和脂滴。相反，NDRG1 表达在营养充足和饥饿条件下最大限度地减少了脂滴的形成。在这里，我们报告说，NDRG1 通过调节表现出脂质代谢表型改变的细胞中脂质的命运来促进乳腺癌的侵袭性。根据其促进髓鞘形成的作用及其与癌症代谢改变的关系，我们的研究结果表明 NDRG1 是乳腺癌细胞脂质命运的关键调节因子。 NDRG1 与乳腺癌不良预后之间的关联表明它应该在患者风险评估中发挥更重要的作用。 NDRG1 在乳腺癌脂质代谢中的功能可能代表着未来一种有前途的治疗方法。本文的在线版本 (10.1186/s13058-018-0980-4) 包含补充材料，可供授权用户使用。
Altered lipid metabolism is an emerging hallmark of aggressive breast cancers. The N-myc downstream regulated gene (NDRG1) gene plays a critical role in peripheral nervous system myelination, as inactivating mutations cause severe demyelinating neuropathy. In breast cancer, elevated NDRG1 expression has been linked to clinical outcomes, but its functional role in breast cancer physiology has remained unclear. A meta-analysis of NDRG1 expression in multiple large publicly available genomic databases was conducted. Genome-wide expression correlation and Cox proportional hazards and Kaplan-Meier modeling of clinical outcomes associated with elevated expression were assessed. To study NDRG1 function, gene silencing and overexpression phenotypic studies were carried out in a panel of cell lines representing all major breast cancer molecular subtypes. Changes in cell proliferation, morphology, and neutral lipid accumulation due to altered NDRG1 expression were assessed by high throughput, quantitative microscopy. Comprehensive lipidomics mass spectrometry was applied to characterize global changes in lipid species due to NDRG1 silencing. Labeled fatty acids were used to monitor cellular fatty acid uptake and subcellular distribution under nutrient replete and starvation culture conditions. NDRG1 overexpression correlated with glycolytic and hypoxia-associated gene expression, and was associated with elevated rates of metastasis and patient mortality. Silencing NDRG1 reduced cell proliferation rates, causing lipid metabolism dysfunction including increased fatty acid incorporation into neutral lipids and lipid droplets. Conversely, NDRG1 expression minimized lipid droplet formation under nutrient replete and starvation conditions. Here we report that NDRG1 contributes to breast cancer aggressiveness by regulating the fate of lipids in cells that exhibit an altered lipid metabolic phenotype. In line with its role in promoting myelination and its association with altered metabolism in cancer, our findings show that NDRG1 is a critical regulator of lipid fate in breast cancer cells. The association between NDRG1 and poor prognosis in breast cancer suggests it should play a more prominent role in patient risk assessment. The function of NDRG1 in breast cancer lipid metabolism may represent a promising therapeutic approach in the future. The online version of this article (10.1186/s13058-018-0980-4) contains supplementary material, which is available to authorized users.
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影响因子：
9.3
作者：
Hu Z;Fan C;Livasy C;He X;Oh DS;Ewend MG;Carey LA;Subramanian S;West R;Ikpatt F;Olopade OI;van de Rijn M;Perou CM
通讯作者：
Perou CM
DOI：
10.1016/j.bbalip.2013.03.011
发表时间：
2013-10
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Baumann J;Sevinsky C;Conklin DS
通讯作者：
Conklin DS
DOI：
10.1074/jbc.m115.682203
发表时间：
2015-10-30
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Boeszoermenyi A;Nagy HM;Arthanari H;Pillip CJ;Lindermuth H;Luna RE;Wagner G;Zechner R;Zangger K;Oberer M
通讯作者：
Oberer M
影响因子：
3.7
作者：
Kachhap SK;Faith D;Qian DZ;Shabbeer S;Galloway NL;Pili R;Denmeade SR;DeMarzo AM;Carducci MA
通讯作者：
Carducci MA
DOI：
10.1073/pnas.1503683112
发表时间：
2015-09-15
影响因子：
11.1
作者：
Croessmann, Sarah;Wong, Hong Yuen;Park, Ben Ho
通讯作者：
Park, Ben Ho