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Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells.

ABSTRACT: Obese breast cancer patients exhibit a higher risk for larger tumor burden and an increased likelyhood of metastasis. The molecular effects of obesity on carcinogenesis are mediated by the autocrine and paracrine effects of the adipocytokine leptin. Leptin participates in the tumor progression and metastasis of human breast. We show that leptin induces clonogenicity and increases the 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 the release of a transcriptionally active Notch1 intracellular domain (NICD). Chromatin immunoprecipitation analysis shows that NICD gets recruited to the survivin promoter at the CSL (CBF1/RBP-Jk, Su(H), Lag-1) binding site in response to leptin treatment. Inhibition of Notch1 activity inhibits leptin-induced survivin upregulation. Leptin-induced transactivation of epidermal growth factor receptor (EGFR) is involved in leptin-mediated Notch1 and survivin upregulation, demonstrating 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, such as 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 strategy. This conclusion is supported by in vivo data showing the overexpression of leptin and survivin in epithelial cells of high-grade ductal carcinomas in situ and in high-grade invasive carcinomas.

SUBMITTER: Knight BB

PROVIDER: S-EPMC3361735 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells.

Knight Brandi B BB Oprea-Ilies Gabriela M GM Nagalingam Arumugam A Yang Lily L Cohen Cynthia C Saxena Neeraj K NK Sharma Dipali D

Endocrine-related cancer 20110701 4

Obese breast cancer patients exhibit a higher risk for larger tumor burden and an increased likelyhood of metastasis. The molecular effects of obesity on carcinogenesis are mediated by the autocrine and paracrine effects of the adipocytokine leptin. Leptin participates in the tumor progression and metastasis of human breast. We show that leptin induces clonogenicity and increases the migration potential of breast cancer cells. We found that survivin expression is induced in response to leptin. I ...[more]

PMID: 21555376

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Project description:BackgroundAberrant activation of Notch signaling has been causally linked to the metastasis of hepatocellular carcinoma (HCC), however the underlying molecular mechanisms are still poorly understood. RING finger protein 187 (RNF187) was recently revealed to be a driver of several cancers, but its expression pattern and biological function in HCC are unknown.MethodsThe expression levels of Notch1 and RNF187 were assessed in two independent cohorts of HCC tissues, and modulation of Notch1 in HCC cells was performed to explore the regulatory role of Notch1 in HCC metastasis. RNA-sequencing (RNA-seq), bioinformatics analysis, luciferase reporter analysis, and chromatin immunoprecipitation assay (ChIP) were used to clarify the relationship between Notch1 signaling and its potential target Ring finger protein 187 (RNF187). Gain- and loss-of-function studies were used to dissect the role of Notch1-RNF187 signaling in promoting HCC metastasis. The impact of Notch1-RNF187 activity in determining clinical prognosis for HCC patients was evaluated by multivariate Cox regression.ResultsBy RNA-seq, luciferase reporter analysis, and ChIP assay, RNF187 was confirmed to be a direct transcriptional target of Notch1, as Notch1 could activate RNF187 promoter whereas the pro-migratory and pro-invasive effects of Notch1 were significantly attenuated by RNF187 knockdown. Meanwhile, RNF187 silencing could attenuate the Notch1-dependent epithelial-mesenchymal transition (EMT). Moreover, overexpression of RNF187 counteracted the inhibitory effect of Notch1 knockdown on cancer progression. Importantly, HCC patients with high level of hepatic Notch1 expression had shorter disease-free survival (DFS) than those with low level of hepatic Notch1 expression. Furthermore, patients with high level of Notch1 and RNF187 co-expression showed the shortest DFS. The expression level of Notch1 and RNF187 was an independent prognostic factor for HCC.ConclusionsFor the first time we identified that RNF187 is an essential factor for Notch1 to promote invasion and metastasis of HCC. Of highly clinical relevance, we found that activation of Notch1-RNF187 correlates with a worse prognosis of HCC patients. These findings provide a solid foundation for developing novel strategies to tackle HCC metastasis.

Dataset Information

Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells.

Publications

Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells.

Similar Datasets

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