miR-199a-3p targets stemness-related and mitogenic signaling pathways to suppress the expansion and tumorigenic capabilities of prostate cancer stem cells.
miR-199a-3p targets stemness-related and mitogenic signaling pathways to suppress the expansion and tumorigenic capabilities of prostate cancer stem cells.
复制标题
miR-199a-3p靶向干性相关和有丝分裂信号通路，抑制前列腺癌干细胞的扩增和致瘤能力
DOI：
10.18632/oncotarget.10652
复制
发表时间：
2016-08-30
期刊：
影响因子：
--
通讯作者：
Tang DG
中科院分区：
文献类型：
--
作者：
Liu R;Liu C;Zhang D;Liu B;Chen X;Rycaj K;Jeter C;Calhoun-Davis T;Li Y;Yang T;Wang J;Tang DG
人类癌症表现出显著的细胞异质性，除了分化较多的子代具有有限的致瘤能力外，还具有致瘤干细胞(CSCs)。最近的研究表明，microRNAs(MiRNAs)调控CSCs和肿瘤的发展。先前对CD44+(和其他)前列腺CSC与非CSC人群中miRNA差异表达的文库筛选发现，miR-199a-3p是CSC中表达最低的miRNAs之一。在这项研究中，我们研究了miR-199a-3p在CD44+前列腺癌(PCa)细胞和肿瘤再生中的生物学功能。在纯化的CD44+细胞或原代PCa细胞中过表达miR-199a-3p可抑制细胞增殖和克隆性扩增，但不诱导细胞凋亡。MIR-199a-3p的过表达也降低了CD44+PCa细胞的肿瘤起始能力以及大量PCa细胞的肿瘤再生。重要的是，NOD/SCID小鼠预先建立的前列腺癌中可诱导的miR-199a-3p表达抑制了肿瘤的生长。利用靶点预测程序和荧光素酶分析，我们从机制上证明CD44是miR-199a-3p在PCa细胞中的直接功能靶点。此外，miR-199a-3p还直接或间接靶向其他几个促分裂分子，包括c-myc、细胞周期蛋白D_1(CCND_1)和EGFR。综上所述，我们的结果表明，miRNA介导的机制的异常丢失如何导致前列腺CSCs的扩张和致瘤活性，进一步支持开发和实施用于癌症治疗的miRNA模拟物。
Human cancers exhibit significant cellular heterogeneity featuring tumorigenic cancer stem cells (CSCs) in addition to more differentiated progeny with limited tumor-initiating capabilities. Recent studies suggest that microRNAs (miRNAs) regulate CSCs and tumor development. A previous library screening for differential miRNA expression in CD44+ (and other) prostate CSC vs. non-CSC populations identified miR-199a-3p to be among the most highly under-expressed miRNAs in CSCs. In this study, we characterized the biological functions of miR-199a-3p in CD44+ prostate cancer (PCa) cells and in tumor regeneration. Overexpression of miR-199a-3p in purified CD44+ or bulk PCa cells, including primary PCa, inhibited proliferation and clonal expansion without inducing apoptosis. miR-199a-3p overexpression also diminished tumor-initiating capacities of CD44+ PCa cells as well as tumor regeneration from bulk PCa cells. Importantly, inducible miR-199a-3p expression in pre-established prostate tumors in NOD/SCID mice inhibited tumor growth. Using target prediction program and luciferase assays, we show mechanistically that CD44 is a direct functional target of miR-199a-3p in PCa cells. Moreover, miR-199a-3p also directly or indirectly targeted several additional mitogenic molecules, including c-MYC, cyclin D1 (CCND1) and EGFR. Taken together, our results demonstrate how the aberrant loss of a miRNA-mediated mechanism can lead to the expansion and tumorigenic activity of prostate CSCs, further supporting the development and implementation of miRNA mimics for cancer treatment.