期刊
CANCER RESEARCH
卷 73, 期 19, 页码 5936-5948出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-0158
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资金
- Fundacao para a Ciencia e Tecnologia, Portugal [SFRH/BD/68267/2010]
- Imperial Experimental Cancer Medicine Centre (ECMC)
- NIHR Imperial Biomedical Research Centre (BRC)
- Association for International Cancer Research (AICR)
- NIHR
- Cancer Research UK
- Medical Research Council
- Association for International Cancer
- Petra University
- British Heart Foundation
- Breast Cancer Campaign
- MRC [G1100425, MR/L000172/1] Funding Source: UKRI
- Fundação para a Ciência e a Tecnologia [SFRH/BD/68267/2010] Funding Source: FCT
- Cancer Research UK [14549] Funding Source: researchfish
- Medical Research Council [G1100425, MR/L000172/1] Funding Source: researchfish
- National Institute for Health Research [NIHR-RP-011-053] Funding Source: researchfish
- Worldwide Cancer Research [10-0510] Funding Source: researchfish
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 a(ER alpha) 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 miR515-5p. Analysis of chromatin immunoprecipitation sequencing (ChIP-Seq) data reveals that miR-515-5p suppression is mediated by a direct interaction of ERa 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 ER alpha, miR-515-5p, proliferation, and apoptosis in breast cancer tumorigenesis. (C) 2013 AACR.
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