Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation
| Autor: | Jonathan Waxman, Loredana Pellegrino, Jonathan Krell, Victoria Harding, Adam E Frampton, Leandro Castellano, Filipa G. Pinho, Heba Alshaker, D. Pchejetski, Laura Roca-Alonso, Justin Stebbing, Joao Nunes, Jimmy Jacob, Alexander de Giorgio |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Antineoplastic Agents Hormonal Blotting Western Estrogen receptor Apoptosis Breast Neoplasms Biology Real-Time Polymerase Chain Reaction medicine.disease_cause Breast cancer Tumor Cells Cultured medicine Humans RNA Messenger Promoter Regions Genetic Cell Proliferation Reverse Transcriptase Polymerase Chain Reaction Estrogen Receptor alpha Wnt signaling pathway Cancer medicine.disease Antiestrogen Molecular biology Gene Expression Regulation Neoplastic MicroRNAs Phosphotransferases (Alcohol Group Acceptor) Tamoxifen Oncology Sphingosine kinase 1 Cancer research biology.protein Female Carcinogenesis medicine.drug |
| Zdroj: | Cancer Research. 73:5936-5948 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Sphingosine kinase 1 (SK1) plays an important role in estrogen-dependent breast tumorigenesis, but its regulation is poorly understood. A subset of microRNAs (miRNA, miR) is regulated by estrogen and contributes to cellular proliferation and cancer progression. Here, we describe that miR-515-5p is transcriptionally repressed by estrogen receptor α (ERα) and functions as a tumor suppressor in breast cancer. Its downregulation enhances cell proliferation and estrogen-dependent SK1 activity, mediated by a reduction of miR-515-5p posttranscriptional repression. Enforced expression of miR-515-5p in breast cancer cells causes a reduction in SK1 activity, reduced cell proliferation, and the induction of caspase-dependent apoptosis. Conversely, opposing effects occur with miR-515-5p inhibition and by SK1 silencing. Notably, we show that estradiol (E2) treatment downregulates miR-515-5p levels, whereas the antiestrogen tamoxifen causes a decrease in SK1, which is rescued by silencing miR-515-5p. Analysis of chromatin immunoprecipitation sequencing (ChIP-Seq) data reveals that miR-515-5p suppression is mediated by a direct interaction of ERα within its promoter. RNA-sequencing (RNA-Seq) analysis of breast cancer cells after overexpressing miR-515-5p indicates that it partly modulates cell proliferation by regulating the Wnt pathway. The clinical implications of this novel regulatory system are shown as miR-515-5p is significantly downregulated in ER-positive (n = 146) compared with ER-negative (n = 98) breast cancers. Overall, we identify a new link between ERα, miR-515-5p, proliferation, and apoptosis in breast cancer tumorigenesis. Cancer Res; 73(19); 5936–48. ©2013 AACR. |
| Databáze: | OpenAIRE |
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