Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFkappaB/HIF-1alpha activation.
Leptin upregulates VEGF in breast cancer via canonic and non-canonical signalling pathways and NFkappaB/HIF-1alpha activation.
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DOI：
10.1016/j.cellsig.2010.05.003
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发表时间：
2010-09
影响因子：
4.8
通讯作者：
Leibovich SJ
中科院分区：
文献类型：
--
作者：
Gonzalez-Perez RR;Xu Y;Guo S;Watters A;Zhou W;Leibovich SJ
血管内皮生长因子（VEGF）和瘦素水平升高与乳腺癌预后不良密切相关。瘦素信号在人和小鼠乳腺肿瘤细胞（MT）中上调VEGF，但具体的分子机制在很大程度上尚不清楚。采用药理学和遗传学方法剖析瘦素对乳腺肿瘤细胞（4T1、EMT6和MMT）中VEGF蛋白和mRNA的调节机制。将一系列VEGF启动子荧光素酶报告基因（全长以及转录因子结合位点缺失的）转染到乳腺肿瘤细胞中，以分析瘦素对VEGF转录的调节。对VEGF启动子的缺失分析和RNA干扰表明，缺氧诱导因子 - 1α（HIF - 1α）和核因子κB（NFκB）对瘦素调节VEGF至关重要。瘦素激活HIF - 1α主要与经典（丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇 - 3 - 激酶（PI - 3K））和非经典（蛋白激酶C（PKC）、c - Jun氨基末端激酶（JNK）和p38丝裂原活化蛋白激酶（p38 MAP））信号通路相关。瘦素的非经典信号通路（JNK、p38 MAP以及在较小程度上的PKC）与NFκB激活相关。特异性蛋白1（SP1）参与4T1细胞中瘦素对VEGF的调节。激活蛋白1（AP1）未参与，而激活蛋白2（AP2）抑制瘦素诱导的VEGF增加。总体而言，这些数据表明瘦素信号主要通过HIF - 1α和NFκB调节VEGF。这些结果描绘了瘦素在乳腺肿瘤细胞中调节VEGF的综合机制。阻断瘦素信号可作为治疗乳腺癌的一种新方法。
High levels of VEGF and leptin are strongly linked to worse prognosis of breast cancer. Leptin signalling up-regulates VEGF in human and mouse mammary tumor cells (MT), but the specific molecular mechanisms are largely unknown. Pharmacologic and genetic approaches were used to dissect the mechanism of leptin regulation of VEGF protein and mRNA in MT (4T1, EMT6 and MMT). A series of VEGF-promoter Luc-reporters (full-length and transcription factor-binding deletions) were transfected into MT to analyze leptin regulation of VEGF transcription. Deletion analysis of VEGF promoter and RNA knockdown shows that HIF-1α and NFκB are essentials for leptin regulation of VEGF. Leptin activation of HIF-1α was mainly linked to canonic (MAPK, PI-3K) and non-canonic (PKC, JNK and p38 MAP) signalling pathways. Leptin non-canonic signalling pathways (JNK, p38 MAP and to less extent PKC) were linked to NFκB activation. SP1 was involved in leptin regulation of VEGF in 4T1 cells. AP1 was not involved and AP2 repressed leptin-induced increase of VEGF. Overall, these data suggest that leptin signalling regulates VEGF mainly through HIF-1α and NFκB. These results delineate a comprehensive mechanism for leptin regulation of VEGF in MT. Disruption of leptin signalling could be used as a novel way to treat breast cancer.
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瘦素信号传导抑制可在雌激素受体阳性或阴性乳腺癌中产生有效的抗肿瘤活性。
影响因子：
7.4
作者：
Gonzalez, Ruben Rene;Watters, Amber;Xu, Yanbo;Singh, Udai P.;Mann, David R.;Rueda, Bo R.;Penichet, Manuel L.
通讯作者：
Penichet, Manuel L.
影响因子：
6.4
作者：
Carino, Cecilia;Olawaiye, Alexander B.;Cherfils, Salandre;Serikawa, Takehiro;Lynch, Maureen P.;Rueda, Bo R.;Gonzalez, Ruben R.
通讯作者：
Gonzalez, Ruben R.
影响因子：
8
作者：
Cascio, S.;Bartella, V.;Surmacz, E.
通讯作者：
Surmacz, E.
影响因子：
4.8
作者：
Gonzalez, RR;Rueda, BR;Leavis, PC
通讯作者：
Leavis, PC
影响因子：
4.8
作者：
Jiang, Lin;Li, Zhiqin;Rui, Liangyou
通讯作者：
Rui, Liangyou