Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Liberalization Ave, No. 1095, Wuhan, 430030, People's Republic of China.
Department of Urology, Peking University First Hospital, Peking University, Beijing, 100034, China.
J Exp Clin Cancer Res. 2018 Sep 5;37(1):219. doi: 10.1186/s13046-018-0895-z.
Previous studies report that miR-1-3p, a member of the microRNA-1 family (miR-1), and functions as a tumor suppressor in several different cancers. However, little is known regarding the biological role and intrinsic regulatory mechanisms of miR-1-3p in prostate cancer (PCa).
In this study, the expression levels of miR-1-3p were first examined in PCa cell lines and tumor tissues by RT-qPCR and bioinformatics. The in vitro and in vivo functional effect of miR-1-3p was examined further. A luciferase reporter assay was conducted to confirm target associations.
We found that miR-1-3p was significantly downregulated in advanced PCa tissues and cell lines. Low miR-1-3p levels were strongly associated with aggressive clinicopathological features and poor prognosis in PCa patients. Ectopic expression of miR-1-3p in 22RV1 and LncaP cells was sufficient to prevent tumor cell growth and cell cycle progression in vitro and in vivo. Further mechanistic studies revealed that miR-1-3p could directly target the mRNA 3'- untranslated region (3'- UTR) of two central cell cycle genes, E2F5 and PFTK1, and could suppress their mRNA and protein expression. In addition, knockdown of E2F5 and PFTK1 mimicked the tumor-suppressive effects of miR-1-3p overexpression on PCa progression. Conversely, concomitant knockdown of miR-1-3p and E2F5 and PFTK1 substantially reversed the inhibitory effects of either E2F5 or PFTK1 silencing alone.
These data highlight an important role for miR-1-3p in the regulation of proliferation and cell cycle in the molecular etiology of PCa and indicate the potential for miR-1-3p in applications furthering PCa prognostics and therapeutics.
先前的研究报告表明，miR-1-3p 是 microRNA-1 家族（miR-1）的成员，在几种不同的癌症中充当肿瘤抑制因子。然而，miR-1-3p 在前列腺癌（PCa）中的生物学作用和内在调节机制知之甚少。
本研究首先通过 RT-qPCR 和生物信息学检测了 miR-1-3p 在 PCa 细胞系和肿瘤组织中的表达水平。进一步研究了 miR-1-3p 的体外和体内功能效应。进行了荧光素酶报告基因测定以确认靶标关联。
我们发现 miR-1-3p 在晚期 PCa 组织和细胞系中显著下调。低 miR-1-3p 水平与 PCa 患者侵袭性临床病理特征和不良预后密切相关。在 22RV1 和 LncaP 细胞中异位表达 miR-1-3p 足以防止体外和体内肿瘤细胞生长和细胞周期进展。进一步的机制研究表明，miR-1-3p 可以直接靶向两个核心细胞周期基因 E2F5 和 PFTK1 的 mRNA 3'-非翻译区（3'-UTR），并可以抑制其 mRNA 和蛋白表达。此外，E2F5 和 PFTK1 的敲低模拟了 miR-1-3p 过表达对 PCa 进展的肿瘤抑制作用。相反，miR-1-3p 和 E2F5 和 PFTK1 的同时敲低大大逆转了单独敲低 E2F5 或 PFTK1 的抑制作用。
这些数据突出了 miR-1-3p 在 PCa 分子发病机制中对增殖和细胞周期的调节作用，并表明 miR-1-3p 在进一步推进 PCa 预后和治疗的应用中的潜力。
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