Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells.
Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells.
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DOI：
10.1530/erc-11-0075
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发表时间：
2011-08
影响因子：
3.9
通讯作者：
Sharma D
中科院分区：
文献类型：
--
作者：
Knight BB;Oprea-Ilies GM;Nagalingam A;Yang L;Cohen C;Saxena NK;Sharma D
肥胖的乳腺癌患者表现出更高的肿瘤负荷和转移增加的风险。肥胖在癌变中的分子效应是由脂肪细胞因子瘦素的自分泌和旁分泌作用介导的。瘦素参与乳腺肿瘤的进展和转移。我们发现瘦素诱导乳腺癌细胞的克隆性和迁移潜力。我们发现瘦素会诱导survivin的表达。在这项研究中，我们研究了瘦素介导的survivin的作用和调控。瘦素治疗导致survivin上调，部分原因是Notch1的激活和转录活性Notch1-胞内结构域（NICD）的释放。ChIP分析显示NICD在瘦素治疗后被募集到csl结合位点的survivin启动子上。Notch1活性抑制瘦素诱导的survivin上调。瘦素诱导的EGFR转激活参与瘦素介导的Notch1和survivin上调，显示出瘦素-EGFR-Notch1轴在上游的新作用。我们进一步表明，瘦素诱导的乳腺癌细胞迁移需要survivin，因为survivin的过度表达会进一步增加，而沉默survivin则会消除瘦素诱导的迁移。通过药理学方法抑制survivin，我们发现3-羟基-3-甲基戊二酰辅酶a -还原酶抑制剂（HRIs）洛伐他汀可以有效抑制瘦素诱导的survivin表达和迁移。重要的是，瘦素增加了裸鼠乳腺肿瘤的生长。这些数据显示了survivin在瘦素诱导的迁移中的新作用，并提出了survivin的药理学抑制作为潜在的新治疗靶点。这一结论得到了高级别导管原位癌和高级别浸润性癌上皮细胞中瘦素和survivin过表达的体内数据的支持。
Obese breast cancer patients exhibit a higher risk for larger tumor burden and increased metastasis. Molecular effects of obesity on carcinogenesis are mediated by autocrine and paracrine effects of adipocytokine leptin. Leptin participates in tumor progression and metastasis of human breast. We show that leptin induces clonogenicity and migration potential of breast cancer cells. We found that survivin expression is induced in response to leptin. In this study, we examine the role and leptin-mediated regulation of survivin. Leptin treatment leads to survivin upregulation, due in part to the activation of Notch1 and release of transcriptionally active Notch1-intracellular-domain (NICD). ChIP analysis show that NICD gets recruited to survivin promoter at CSL-binding-site in response to leptin treatment. Inhibition of Notch1 activity inhibits leptin-induced survivin upregulation. Leptin-induced transactivation of EGFR is involved in leptin-mediated Notch1 and survivin upregulation showing a novel upstream role of leptin-EGFR-Notch1 axis. We further show that leptin-induced migration of breast cancer cells requires survivin, as overexpression of survivin further increases, whereas silencing survivin abrogates leptin-induced migration. Using a pharmacological approach to inhibit survivin, we show that 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors (HRIs), lovastatin, can effectively inhibit leptin-induced survivin expression and migration. Importantly, leptin increased breast tumor growth in nude mice. These data show a novel role for survivin in leptin-induced migration and put forth pharmacological survivin inhibition as a potential novel therapeutic target. This conclusion is supported by in vivo data showing overexpression of leptin and survivin in epithelial cells of high grade ductal carcinoma in situ and high grade invasive carcinoma.