Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting.
Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting.
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DOI：
10.1186/s13046-016-0317-z
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发表时间：
2016-03-15
期刊：
影响因子：
--
通讯作者：
Yuan Z
中科院分区：
文献类型：
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作者：
Huang XY;Huang ZL;Yang JH;Xu YH;Sun JS;Zheng Q;Wei C;Song W;Yuan Z
骨骼肌的进行性损失，称为肌肉萎缩，是癌症恶病质的标志，并导致虚弱，生活质量下降，以及对治疗的反应差。先前的研究表明，与肿瘤发展相关的全身性宿主炎症反应导致肌肉萎缩。然而，肿瘤如何通过肿瘤源性分泌蛋白直接调节肌肉萎缩仍然是未知的。在这项研究中，我们对胰腺导管腺癌的两个数据集进行了生物信息学分析，胰腺导管腺癌导致癌症恶病质和肌肉萎缩的患病率最高，并发现编码IGF结合蛋白-3（IGFBP-3）的IGFBP 3在胰腺肿瘤样本中显著上调。我们还通过生化和遗传分析验证了IGFBP-3对C2 C12肌细胞的消耗作用。IGFBP-3通过IGF信号传导抑制有效地导致受损的肌生成和增强的肌肉蛋白降解，这是肌肉萎缩的主要特征。此外，来自Capan-1胰腺癌细胞的条件培养基（其含有丰富的IGFBP-3）显著诱导肌肉细胞消耗。这种消耗作用通过在Capan-1细胞中的IGFBP-3敲低或IGFBP-3抗体中和而有效地减轻。引人注目的是，与肌肉细胞相比，IGF信号传导和Capan-1细胞的增殖速率很少受到IGFBP-3处理的影响。我们的研究结果表明，胰腺癌细胞通过产生IGFBP-3诱导肌肉萎缩。本文的在线版本（doi：10.1186/s13046-016-0317-z）包含补充材料，可供授权用户使用。
Progressive loss of skeletal muscle, termed muscle wasting, is a hallmark of cancer cachexia and contributes to weakness, reduced quality of life, as well as poor response to therapy. Previous studies have indicated that systemic host inflammatory response regarding tumor development results in muscle wasting. However, how tumor directly regulates muscle wasting via tumor-derived secreted proteins is still largely unknown. In this study, we performed bioinformatics analysis in two datasets of pancreatic ductal adenocarcinoma, which causes cancer cachexia and muscle wasting with the highest prevalence, and uncovered that IGFBP3, which encodes IGF-binding protein-3 (IGFBP-3), is dramatically up-regulated in pancreatic tumor samples. We also verified the wasting effect of IGFBP-3 on C2C12 muscle cells with biochemical and genetic assays. IGFBP-3 potently leads to impaired myogenesis and enhanced muscle protein degradation, the major features of muscle wasting, via IGF signaling inhibition. Moreover, conditioned medium from Capan-1 pancreatic cancer cells, which contains abundant IGFBP-3, significantly induces muscle cell wasting. This wasting effect is potently alleviated by IGFBP3 knockdown in Capan-1 cells or IGFBP-3 antibody neutralization. Strikingly, compared to muscle cells, IGF signaling and proliferation rate of Capan-1 cells were rarely affected by IGFBP-3 treatment. Our results demonstrated that pancreatic cancer cells induce muscle wasting via IGFBP-3 production. The online version of this article (doi:10.1186/s13046-016-0317-z) contains supplementary material, which is available to authorized users.