Notch, IL-1 and leptin crosstalk outcome (NILCO) is critical for leptin-induced proliferation, migration and VEGF/VEGFR-2 expression in breast cancer.
Notch, IL-1 and leptin crosstalk outcome (NILCO) is critical for leptin-induced proliferation, migration and VEGF/VEGFR-2 expression in breast cancer.
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DOI：
10.1371/journal.pone.0021467
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Gonzalez-Perez RR
中科院分区：
文献类型：
--
作者：
Guo S;Gonzalez-Perez RR
在乳腺癌中发现高水平的促血管生成因子，瘦素，IL-1，Notch和VEGF（配体和受体），其通常与转移和患者的较低存活率相关。我们曾报道瘦素诱导乳腺癌的生长及VEGF/VEGFR-2和IL-1系统的表达。我们假设Notch，IL-1和瘦素串扰结果（NILCO）在乳腺癌中瘦素介导的增殖/迁移诱导和促血管生成分子表达的调节中起着重要作用。为了验证这一假设，在小鼠（4 T1、EMT 6和MMT）乳腺癌细胞中测定了瘦素对Notch信号通路和VEGF/VEGFR-2/IL-1的表达和活化的影响。值得注意的是，瘦素上调Notch 1 -4/JAG 1/Dll-4，Notch靶基因：Hey 2和生存素，以及IL-1和VEGF/VEGFR-2。RNA敲除和瘦素信号传导的药物抑制剂显著消除报告基因-荧光素酶CSL（RBP-Jk）启动子的活性，表明其与瘦素激活的JAK 2/STAT 3、MAPK、PI-3 K/mTOR、p38和JNK信号传导通路相关。有趣的是，瘦素对细胞增殖/迁移和促血管生成因子Notch、IL-1和VEGF/VEGFR-2的上调作用被γ-分泌酶抑制剂DAPT以及针对CSL的siRNA消除。此外，阻断IL-1 R tI抑制瘦素诱导的Notch、Hey 2和生存素以及VEGF/VEGFR-2表达。这些数据表明瘦素是Notch（表达/活化）的诱导剂，并且IL-1信号传导调节瘦素对Notch和VEGF/VEGFR-2的作用。我们第一次发现了Notch、IL-1和瘦素（NILCO）之间的一种新的公开的串扰发生在乳腺癌中。乳腺癌细胞中瘦素诱导的增殖/迁移和VEGF/VEGFR-2的上调与完整的Notch信号轴相关。NILCO可能代表了乳腺癌中瘦素诱导的细胞增殖/迁移和VEGF/VEGFR-2调节的关键发育、促炎和促血管生成信号的整合。靶向NILCO可能有助于设计旨在控制乳腺癌生长和血管生成的新药理学策略。
High levels of pro-angiogenic factors, leptin, IL-1, Notch and VEGF (ligands and receptors), are found in breast cancer, which is commonly correlated with metastasis and lower survival of patients. We have previously reported that leptin induces the growth of breast cancer and the expression of VEGF/VEGFR-2 and IL-1 system. We hypothesized that Notch, IL-1 and leptin crosstalk outcome (NILCO) plays an essential role in the regulation of leptin-mediated induction of proliferation/migration and expression of pro-angiogenic molecules in breast cancer. To test this hypothesis, leptin's effects on the expression and activation of Notch signaling pathway and VEGF/VEGFR-2/IL-1 were determined in mouse (4T1, EMT6 and MMT) breast cancer cells. Remarkably, leptin up-regulated Notch1-4/JAG1/Dll-4, Notch target genes: Hey2 and survivin, together with IL-1 and VEGF/VEGFR-2. RNA knockdown and pharmacological inhibitors of leptin signaling significantly abrogated activity of reporter gene-luciferase CSL (RBP-Jk) promoter, showing that it was linked to leptin-activated JAK2/STAT3, MAPK, PI-3K/mTOR, p38 and JNK signaling pathways. Interestingly, leptin upregulatory effects on cell proliferation/migration and pro-angiogenic factors Notch, IL-1 and VEGF/VEGFR-2 were abrogated by a γ-secretase inhibitor, DAPT, as well as siRNA against CSL. In addition, blockade of IL-1R tI inhibited leptin-induced Notch, Hey2 and survivin as well as VEGF/VEGFR-2 expression. These data suggest leptin is an inducer of Notch (expression/activation) and IL-1 signaling modulates leptin effects on Notch and VEGF/VEGFR-2. We show for the first time that a novel unveiled crosstalk between Notch, IL-1 and leptin (NILCO) occurs in breast cancer. Leptin induction of proliferation/migration and upregulation of VEGF/VEGFR-2 in breast cancer cells were related to an intact Notch signaling axis. NILCO could represent the integration of developmental, pro-inflammatory and pro-angiogenic signals critical for leptin-induced cell proliferation/migration and regulation of VEGF/VEGFR-2 in breast cancer. Targeting NILCO might help to design new pharmacological strategies aimed at controlling breast cancer growth and angiogenesis.