Chen Daohong, Goswami Chirayu P, Burnett Riesa M, Anjanappa Manjushree, Bhat-Nakshatri Poornima, Muller William, Nakshatri Harikrishna
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana.
Cancer Res. 2014 Aug 15;74(16):4270-81. doi: 10.1158/0008-5472.CAN-13-2817. Epub 2014 Jun 30.
Circulating microRNAs (miRNA) are emerging as important biomarkers of various diseases, including cancer. Intriguingly, circulating levels of several miRNAs are lower in patients with cancer compared with healthy individuals. In this study, we tested the hypothesis that a circulating miRNA might serve as a surrogate of the effects of cancer on miRNA expression or release in distant organs. Here we report that circulating levels of the muscle-enriched miR486 is lower in patients with breast cancer compared with healthy individuals and that this difference is replicated faithfully in MMTV-PyMT and MMTV-Her2 transgenic mouse models of breast cancer. In tumor-bearing mice, levels of miR486 were relatively reduced in muscle, where there was elevated expression of the miR486 target genes PTEN and FOXO1A and dampened signaling through the PI3K/AKT pathway. Skeletal muscle expressed lower levels of the transcription factor MyoD, which controls miR486 expression. Conditioned media (CM) obtained from MMTV-PyMT and MMTV-Her2/Neu tumor cells cultured in vitro were sufficient to elicit reduced levels of miR486 and increased PTEN and FOXO1A expression in C2C12 murine myoblasts. Cytokine analysis implicated tumor necrosis factor α (TNFα) and four additional cytokines as mediators of miR486 expression in CM-treated cells. Because miR486 is a potent modulator of PI3K/AKT signaling and the muscle-enriched transcription factor network in cardiac/skeletal muscle, our findings implicated TNFα-dependent miRNA circuitry in muscle differentiation and survival pathways in cancer.
循环微RNA（miRNA）正成为包括癌症在内的各种疾病的重要生物标志物。有趣的是，与健康个体相比，癌症患者中几种miRNA的循环水平较低。在本研究中，我们检验了一种假设，即循环miRNA可能作为癌症对远处器官中miRNA表达或释放影响的替代指标。我们在此报告，与健康个体相比，乳腺癌患者中肌肉富集的miR486的循环水平较低，并且这种差异在MMTV-PyMT和MMTV-Her2乳腺癌转基因小鼠模型中得到了准确重现。在荷瘤小鼠中，miR486在肌肉中的水平相对降低，其中miR486靶基因PTEN和FOXO1A的表达升高，并且通过PI3K/AKT途径的信号传导受到抑制。骨骼肌中控制miR486表达的转录因子MyoD表达水平较低。从体外培养的MMTV-PyMT和MMTV-Her2/Neu肿瘤细胞获得的条件培养基（CM）足以使C2C12小鼠成肌细胞中miR486水平降低，并使PTEN和FOXO1A表达增加。细胞因子分析表明肿瘤坏死因子α（TNFα）和另外四种细胞因子是CM处理细胞中miR486表达的介质。由于miR486是心脏/骨骼肌中PI3K/AKT信号传导和肌肉富集转录因子网络的有效调节剂，我们的研究结果表明TNFα依赖性miRNA通路参与了癌症中肌肉分化和存活途径。
