Ramalho-Carvalho João, Martins João Barbosa, Cekaite Lina, Sveen Anita, Torres-Ferreira Jorge, Graça Inês, Costa-Pinheiro Pedro, Eilertsen Ina Andrassy, Antunes Luís, Oliveira Jorge, Lothe Ragnhild A, Henrique Rui, Jerónimo Carmen
Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Biomedical Sciences Graduate Program, Institute of Biomedical Sciences Abel Salazar - University of Porto (ICBAS-UP), Porto, Portugal.
Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
Cancer Lett. 2017 Jan 28;385:150-159. doi: 10.1016/j.canlet.2016.10.028. Epub 2016 Oct 27.
MicroRNAs (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing, fine tuning gene expression. In an initial screen, miRNAs were found to be globally down-regulated in prostate cancer (PCa) cell lines and primary tumours. Exposure of PCa cell lines to a demethylating agent, 5-Aza-CdR resulted in an increase in the expression levels of miRNAs in general. Using stringent filtering criteria miR-130a was identified as the most promising candidate and selected for validation analyses in our patient series. Down-regulation of miR-130a was associated with promoter hypermethylation. MiR-130a methylation levels discriminated PCa from non-malignant tissues (AUC = 0.956), and urine samples revealed high specificity for non-invasive detection of patients with PCa (AUC = 0.89). Additionally, repressive histone marks were also found in the promoter of miR-130a. Over-expression of miR-130a in PCa cells reduced cell viability and invasion capability, and increased apoptosis. Putative targets of miR-130a were assessed by microarray expression profiling and DEPD1C and SEC23B were selected for validation. Silencing of both genes resembled the effect of over-expressing miR-130a in PCa cells. Our data indicate that miR-130a is an epigenetically regulated miRNA involved in regulation of key molecular and phenotypic features of prostate carcinogenesis, acting as a tumour suppressor miRNA.
微小RNA（miRNA）是一类小的非编码RNA，可介导转录后基因沉默，精细调节基因表达。在初步筛选中，发现miRNA在前列腺癌细胞系和原发性肿瘤中整体下调。将前列腺癌细胞系暴露于去甲基化剂5-氮杂-2'-脱氧胞苷（5-Aza-CdR）后，miRNA的表达水平总体上有所增加。使用严格的筛选标准，miR-130a被确定为最有前景的候选者，并在我们的患者系列中进行验证分析。miR-130a的下调与启动子高甲基化有关。miR-130a甲基化水平可区分前列腺癌与非恶性组织（曲线下面积[AUC]=0.956），尿液样本对前列腺癌患者的非侵入性检测具有高特异性（AUC=0.89）。此外，在miR-130a的启动子中也发现了抑制性组蛋白标记。在前列腺癌细胞中过表达miR-130a可降低细胞活力和侵袭能力，并增加细胞凋亡。通过微阵列表达谱评估miR-130a的潜在靶标，并选择DEPD1C和SEC23B进行验证。这两个基因的沉默类似于在前列腺癌细胞中过表达miR-130a的效果。我们的数据表明，miR-130a是一种受表观遗传调控的miRNA，参与前列腺癌发生关键分子和表型特征的调控，起到肿瘤抑制性miRNA的作用。
