Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate.
Characterization and Evidence of the miR-888 Cluster as a Novel Cancer Network in Prostate.
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DOI：
10.1158/1541-7786.mcr-17-0321
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Esquela-Kerscher A
中科院分区：
文献类型：
--
作者：
Hasegawa T;Glavich GJ;Pahuski M;Short A;Semmes OJ;Yang L;Galkin V;Drake R;Esquela-Kerscher A
七分之一的男性患有前列腺癌，是美国男性癌症相关死亡的第二大原因。MicroRNAs （miRNAs）是一类广泛的约22个核苷酸的非编码rna，经常在前列腺癌患者的组织和液体中异常表达，但特异性miRNAs如何调节前列腺肿瘤发生和转移的机制尚不清楚。在这里，miR-888被确定为一种促进增殖和迁移的新型前列腺因子。miR-888位于人类Xq27.3染色体上由7个miRNA基因（mir-892c、mir-890、miR-888、mir-892a、mir-892b、mir-891b、mir-891a）组成的基因组簇中。此外，由于miR-888也位于与易感性和/或遗传性前列腺癌相关的基因座HPCX1中，因此假设其他miRNA簇成员也在前列腺中发挥功能作用。表达分析表明，聚类成员在转移性PC3-ML前列腺细胞及其分泌的外泌体中也同样升高，在临床高级别前列腺癌患者的尿衍生的表达前列腺分泌物（EPS）外泌体中也富集。体外实验显示，miR-888簇成员选择性地调节pc3衍生和LNCaP细胞的增殖、迁移、侵袭和集落形成。小鼠异种移植研究证实miR-888和miR-891a是促进前列腺肿瘤生长的促癌因子。进一步分析证实RBL1、KLF5、SMAD4和TIMP2是miR-888的直接靶点，TIMP2也受miR-891a的共同调控。这项研究首次对整个miR-888簇进行了全面分析，并揭示了生物学的见解。这项工作揭示了前列腺中复杂的非编码RNA网络，可以作为晚期前列腺癌的有效诊断和治疗工具。
Prostate cancer afflicts 1 in 7 men and is the second leading cause of male cancer-related deaths in the United States. MicroRNAs (miRNAs), an extensive class of ~22 nucleotide non-coding RNAs, are often aberrantly expressed in tissues and fluids from prostate cancer patients but the mechanism of how specific miRNAs regulate prostate tumorigenesis and metastasis are poorly understood. Here, miR-888 was identified as a novel prostate factor that promotes proliferation and migration. miR-888 resides within a genomic cluster of 7 miRNA genes (mir-892c, mir-890, mir-888, mir-892a, mir-892b, mir-891b, mir-891a) on human chromosome Xq27.3. Moreover, as miR-888 also maps within HPCX1, a locus associated with susceptibility and/or hereditary prostate cancer, it was hypothesized that additional miRNA cluster members also play functional roles in the prostate. Expression analysis determined that cluster members were similarly elevated in metastatic PC3-ML prostate cells and their secreted exosomes, as well as enriched in expressed prostatic secretions (EPS) urine derived-exosomes obtained from clinical patients with high-grade prostate cancer. In vitro assays revealed that miR-888 cluster members selectively modulated PC3-derived and LNCaP cell proliferation, migration, invasion, and colony formation. Mouse xenograft studies verified miR-888 and miR-891a as pro-oncogenic factors that increased prostate tumor growth in vivo. Further analysis validated RBL1, KLF5, SMAD4 and TIMP2 as direct miR-888 targets and that TIMP2 is also co-regulated by miR-891a. This study provides the first comprehensive analysis of the entire miR-888 cluster and reveals biological insight. This work reveals a complex non-coding RNA network in the prostate that could be developed as effective diagnostic and therapeutic tools for advanced prostate cancer.
影响因子：
3.7
作者：
Kouprina, Natalay;Lee, Nicholas C. O.;Pavlicek, Adam;Samoshkin, Alexander;Kim, Jung-Hyun;Lee, Hee-Sheung;Varma, Sudhir;Reinhold, William C.;Otstot, John;Solomon, Greg;Davis, Sean;Meltzer, Paul S.;Schleutker, Johanna;Larionov, Vladimir
通讯作者：
Larionov, Vladimir