Cancer affects microRNA expression, release, and function in cardiac and skeletal muscle.
Cancer affects microRNA expression, release, and function in cardiac and skeletal muscle.
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DOI：
10.1158/0008-5472.can-13-2817
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发表时间：
2014-08-15
期刊：
影响因子：
11.2
通讯作者：
Nakshatri H
中科院分区：
文献类型：
--
作者：
Chen D;Goswami CP;Burnett RM;Anjanappa M;Bhat-Nakshatri P;Muller W;Nakshatri H
循环microRNA正在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microRNA的循环水平较低。在这项研究中，我们测试了一个假设，即循环microRNA可能作为癌症对microRNA表达或释放在远处器官的影响的替代品。在这里，我们报告了与健康个体相比，乳腺癌患者中肌肉富集的miR-486的循环水平较低，并且这种差异在乳腺癌的MMTV-PyMT和MMTV-Her 2转基因小鼠模型中忠实地复制。在荷瘤小鼠中，肌肉中miR-486的水平相对降低，其中miR-486靶基因PTEN和FOXO 1A的表达升高，并通过PI 3 K/AKT途径抑制信号传导。骨骼肌表达较低水平的控制miR-486表达的转录因子MyoD。从体外培养的MMTV-PyMT和MMTV-Her 2/Neu肿瘤细胞获得的条件培养基（CM）足以引起C2 C12鼠成肌细胞中miR-486水平降低和PTEN和FOXO 1A表达增加。细胞因子分析表明TNFα和另外四种细胞因子是CM处理细胞中miR-486表达的介质。由于miR-486是PI 3 K/AKT信号传导和心肌/骨骼肌中肌肉富集的转录因子网络的有效调节剂，我们的研究结果涉及肿瘤坏死因子α依赖性miRNA回路在肌肉分化和癌症存活途径中的作用。
Circulating microRNAs are emerging as important biomarkers of various diseases including cancer. Intriguingly, circulating levels of several microRNAs are lower in cancer patients compared with healthy individuals. In this study, we tested the hypothesis that a circulating microRNA might serve as a surrogate of the effects of cancer on microRNA expression or release in distant organs. Here we report that circulating levels of the muscle-enriched miR-486 is lower in breast cancer patients 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 miR-486 were relatively reduced in muscle, where there was elevated expression of the miR-486 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 miR-486 expression. Conditioned media (CM) obtained from MMTV-PyMT and MMTV-Her2/Neu tumor cells cultured in vitro was sufficient to elicit reduced levels of miR-486 and increased PTEN and FOXO1A expression in C2C12 murine myoblasts. Cytokine analysis implicated TNFα and four additional cytokines as mediators of miR-486 expression in CM-treated cells. Since miR-486 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.