miR-34c is downregulated in prostate cancer and exerts tumor suppressive functions
miR-34c is downregulated in prostate cancer and exerts tumor suppressive functions
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DOI：
10.1002/ijc.25269
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发表时间：
2010-12-15
影响因子：
6.4
通讯作者：
Ceder, Yvonne
中科院分区：
文献类型：
--
作者：
Hagman, Zandra;Larne, Olivia;Ceder, Yvonne
MicroRNAs(MiRNAs)是一种小的非编码RNA，在转录后调节基因的表达。已经有几个关于miRNA在前列腺癌(PCa)中失控的报道，并且越来越多的生物学证据表明miRNAs参与了前列腺癌的发生。在这项研究中，我们通过对49例前列腺癌患者和25例良性前列腺增生症患者的TURP进行定量逆转录聚合酶链式反应，发现miR-34c在前列腺癌中表达下调(p=0.0005)。MiR-34c的表达与肿瘤的侵袭性、WHO分级、PSA水平及有无转移呈负相关。此外，卡普兰-迈耶根据miR-34c表达水平分为低表达(50%)和高表达(50%)对患者生存进行分析，将患者显著分为高风险和低风险患者(p=0.0003，对数等级检验)。在前列腺细胞系中研究了miR-34c解除调控的表型效应，其中miR-34c的异位表达降低了细胞生长，原因是细胞增殖率下降和细胞凋亡率增加。与此相一致的是，miR-34c被发现负调控癌基因E2F3和bcl2，它们分别促进PCa细胞的增殖和抑制细胞的凋亡。相反，我们也可以证明在体外阻断miR-34c可以促进细胞生长。此外，异位表达miR-34c可以抑制细胞的迁移和侵袭。我们的发现为miR-34c在前列腺中的作用提供了新的见解，显示出对增殖、凋亡和侵袭性的肿瘤抑制作用。
MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression. There have been several reports of miRNA deregulation in prostate cancer (PCa) and the biological evidence for an involvement of miRNAs in prostate tumorigenesis is increasing. In this study, we show that miR-34c is downregulated in PCa (p = 0.0005) by performing qRT-PCR on 49 TURPs from PCa patients compared to 25 from patients with benign prostatic hyperplasia. The miR-34c expression was found to inversely correlate to aggressiveness of the tumor, WHO grade, PSA levels and occurrence of metastases. Furthermore, a Kaplan-Meier analysis of patient survival based on miR-34c expression levels divided into low (< 50th percentile) and high (> 50th percentile) expression, significantly divides the patients into high risk and low risk patients (p = 0.0003, log-rank test). The phenotypic effects of miR-34c deregulation were studied in prostate cell lines, where ectopic expression of miR-34c decreased cell growth, due to both a decrease in cellular proliferation rate and an increase in apoptosis. In concordance to this, miR-34c was found to negatively regulate the oncogenes E2F3 and BCL-2, which stimulates proliferation and suppress apoptosis in PCa cells, respectively. Reversely, we could also show that blocking miR-34c in vitro increases cell growth. Further, ectopic expression of miR-34c was found to suppress migration and invasion. Our findings provide new insight into the role of miR-34c in the prostate, exhibiting tumor suppressing effects on proliferation, apoptosis and invasiveness.