Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, Malmö, Sweden.
Br J Cancer. 2013 Sep 3;109(5):1271-8. doi: 10.1038/bjc.2013.449. Epub 2013 Aug 6.
The microRNA, miR-34c, is a well-established regulator of tumour suppression. It is downregulated in most forms of cancers and inhibits malignant growth by repressing genes involved in processes such as proliferation, anti-apoptosis, stemness, and migration. We have previously reported downregulation and tumour suppressive properties for miR-34c in prostate cancer (PCa).
In this study, we set out to further characterize the mechanisms by which miR-34c deregulation contributes to PCa progression. The genes regulated by miR-34c in the PCa cell line PC3 were identified by microarray analyses and were found to be enriched in cell death, cell cycle, cellular growth, and cellular movement pathways. One of the identified targets was MET, a receptor tyrosine kinase activated by hepatocyte growth factor, that is crucial for metastatic progression.
We confirmed the inhibitory effect of miR-34c on both MET transcript and protein levels. The binding of miR-34c to two binding sites in the 3'-UTR of MET was validated using luciferase reporter assays and target site blockers. The effect of this regulation on the miR-34c inhibition of the migratory phenotype was also confirmed. In addition, a significant inverse correlation between miR-34c expression levels and MET immunostaining was found in PCa patients.
These findings provide a novel molecular mechanism of MET regulation in PCa and contribute to the increasing evidence that miR-34c has a key tumour suppressive role in PCa.
microRNA（miR-34c）是一种成熟的肿瘤抑制因子。它在大多数癌症形式中下调，并通过抑制参与增殖、抗凋亡、干细胞特性和迁移等过程的基因来抑制恶性生长。我们之前已经报道了 miR-34c 在前列腺癌（PCa）中的下调和肿瘤抑制特性。
在这项研究中，我们旨在进一步研究 miR-34c 失调对 PCa 进展的作用机制。通过微阵列分析鉴定了 miR-34c 在 PCa 细胞系 PC3 中调节的基因，这些基因富集在细胞死亡、细胞周期、细胞生长和细胞运动途径中。鉴定的一个靶标是 MET，一种由肝细胞生长因子激活的受体酪氨酸激酶，对转移进展至关重要。
我们证实了 miR-34c 对 MET 转录本和蛋白水平的抑制作用。通过荧光素酶报告基因测定和靶位点阻断剂验证了 miR-34c 与 MET 3'-UTR 两个结合位点的结合。还证实了这种调节对 miR-34c 抑制迁移表型的影响。此外，在 PCa 患者中发现 miR-34c 表达水平与 MET 免疫染色呈显著负相关。
这些发现为 PCa 中 MET 调节的新分子机制提供了依据，并为越来越多的证据表明 miR-34c 在 PCa 中具有关键的肿瘤抑制作用做出了贡献。
