Authors' Affiliations: Division of Oncology, Department of Surgery & Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM); Department of Medicine and HPB Surgical Unit, Department of Surgery & Cancer, Imperial College; Department of Oncology, Imperial College Healthcare NHS Trust, Charing Cross Hospital, London; and School of Medicine, University of East Anglia, Norwich, United Kingdom.
Cancer Res. 2013 Oct 1;73(19):5936-48. doi: 10.1158/0008-5472.CAN-13-0158. Epub 2013 Aug 8.
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.
丝氨酸苏氨酸激酶 1（SK1）在雌激素依赖性乳腺癌发生中发挥重要作用，但对其调控知之甚少。一小部分 microRNA（miRNA，miR）受雌激素调控，并促进细胞增殖和癌症进展。在这里，我们描述了 miR-515-5p 受雌激素受体α（ERα）转录抑制，并在乳腺癌中作为肿瘤抑制因子发挥作用。其下调增强了细胞增殖和雌激素依赖性 SK1 活性，这是通过 miR-515-5p 转录后抑制的减少介导的。在乳腺癌细胞中强制表达 miR-515-5p 会导致 SK1 活性降低、细胞增殖减少和 caspase 依赖性细胞凋亡诱导。相反，miR-515-5p 抑制和 SK1 沉默会产生相反的效果。值得注意的是，我们表明，雌二醇（E2）处理下调 miR-515-5p 水平，而抗雌激素他莫昔芬导致 SK1 减少，这可以通过沉默 miR-515-5p 来挽救。染色质免疫沉淀测序（ChIP-Seq）数据的分析揭示了 miR-515-5p 的抑制是由 ERα 在其启动子内的直接相互作用介导的。在过表达 miR-515-5p 的乳腺癌细胞中进行 RNA 测序（RNA-Seq）分析表明，它部分通过调节 Wnt 通路来调节细胞增殖。该新型调控系统的临床意义表明，miR-515-5p 在 ER 阳性（n = 146）乳腺癌中明显下调，而在 ER 阴性（n = 98）乳腺癌中下调（n = 146）。总体而言，我们确定了 ERα、miR-515-5p、增殖和凋亡在乳腺癌发生中的新联系。
