Negative regulation of UCP2 by TGFβ signaling characterizes low and intermediate-grade primary breast cancer.
Negative regulation of UCP2 by TGFβ signaling characterizes low and intermediate-grade primary breast cancer.
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DOI：
10.1038/cddis.2010.30
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发表时间：
2010-07-15
影响因子：
9
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中科院分区：
文献类型：
--
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肿瘤细胞中生长调节和分化诱导信号的组织学表现被认为是临床预后预测的关键组成部分，通常定义为肿瘤分化等级。然而，这一临床参数背后的分子和功能框架仍然知之甚少。我们的相关数据显示，线粒体解偶联蛋白2 （UCP2）与原发性乳腺癌的肿瘤分级之间存在显著相关性（P < 0.001） （n=234）。通过机制分析，我们发现UCP2和已建立的细胞通路在赋予等级相关功能表型方面存在协同联系。在这里，将well应用于中等分化的原发肿瘤细胞系，可以直接观察到SMAD募集到UCP2启动子，从而抑制基因转录。相比之下，低分化的肿瘤细胞，已知是TGFβ耐药，表现出异常的UCP2调控，因此，基因过表达，减少线粒体钙，促进线粒体膜电位的维持，从而显著降低氧化应激和抑制细胞死亡。相反，在这些细胞中，UCP2沉默迅速导致细胞凋亡和细胞分化，同时细胞存活和增殖降低，证实了基因特异性作用。证明UCP2失调在促进肿瘤侵袭性的多种特征中的生物学驱动作用，强烈支持在临床表现时评估基因表达，以增强治疗决策，并通过个性化靶向方法改善患者预后。
The histological manifestation of growth-regulating and differentiation-inducing signals in cancer cells is considered as a key component for clinical outcome prediction and commonly defined as tumor differentiation grade. However, the molecular and functional framework underlying this clinical parameter remains poorly understood. Our correlative data display a significant association (P>0.001) between mitochondrial uncoupling protein 2 (UCP2) and tumor grade in primary breast cancer (n=234). Through mechanistic analyses, we show a synergistic link between UCP2 and established cellular pathways in conferring grade-associated functional phenotypes. Here, the application of well to moderately differentiated primary tumor cell lines has enabled direct observation of SMAD recruitment to the UCP2 promoter underlying repression of gene transcription. In contrast, poorly differentiated tumor cells, known to be TGFβ resistant, displayed aberrant UCP2 regulation, and consequently, gene overexpression, which reduced mitochondrial calcium and facilitated the maintenance of mitochondrial membrane potential, thereby significantly decreasing oxidative stress and inhibiting cell death. Conversely, UCP2 silencing in such cells rapidly led to the induction of apoptosis and cell differentiation, concurrent with reduced cell survival and proliferation, confirming gene-specific effects. Demonstration of a biologically driven role for UCP2 dysregulation in promoting multiple characteristics of tumor aggressiveness strongly endorses assessment of gene expression at clinical presentation to augment therapeutic decision-making and improve patient outcome through personalized targeting approaches.
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影响因子：
4.7
作者：
Derdák, Z;Fülöp, P;Baffy, G
通讯作者：
Baffy, G
影响因子：
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Minagawa, N;Kruglov, EA;Nathanson, MH
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Nathanson, MH
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NegreSalvayre, A;Hirtz, C;Casteilla, L
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Casteilla, L
影响因子：
20.1
作者：
Lee, KU;Lee, IK;Park, JY
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Park, JY
影响因子：
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作者：
HAJNOCZKY, G;ROBBGASPERS, LD;THOMAS, AP
通讯作者：
THOMAS, AP