Abstract：
Cachexia is associated with poor prognosis in cancer patients, and inflammation is one of its main drive factors. MicroRNAs have recently emerged as important players in cancer cachexia and are involved in reciprocal regulation networks with pro-inflammatory signaling pathways. We hypothesize that inflammation-driven cancer cachexia is regulated by specific microRNAs. The aim of this study is to explore the expression and role of inflammation-related microRNAs in muscle wasting. HPV16-transgenic mice develop systemic inflammation and muscle wasting and are a model for cancer cachexia. We employed gastrocnemius muscle samples from these mice to study the expression of microRNAs. Bioinformatic tools were then used to explore their potential role in muscle wasting. Among the microRNAs studied, miR-223-3p (p = 0.004), let-7b-5p (p = 0.034), miR-21a-5p (p = 0.034), miR-150-5p (p = 0.027), and miR-155-5p (p = 0.011) were significantly upregulated in muscles from cachectic mice. In silico analysis showed that these microRNAs participate in several processes related to muscle wasting, including muscle structure development and regulation of the MAPK pathway. When analyzing protein-protein interactions (PPI)-networks, two major clusters and the top 10 hubs were obtained. From the top 10, Kras (p = 0.050) and Ccdn1 (p = 0.009) were downregulated in cachectic muscles, as well as Map2k3 (p = 0.007). These results show that miR-223-3p, let-7b-5p, miR-21a-5p, miR-150-5p, and miR-155-5p, play a role in muscle wasting in HPV16 transgenic mice, possible through regulating the MAPK cascades. Future experimental studies are required to validate our in silico analysis, and to explore the usefulness of these microRNAs and MAPK signaling as new potential biomarkers or therapy targets for cancer cachexia.
摘要：
恶病质与癌症患者的不良预后有关，炎症是其主要驱动因素之一。MicroRNAs最近已成为癌症恶病质的重要参与者，并参与与促炎信号通路的相互调节网络。我们假设炎症驱动的癌症恶病质受特定microRNA调节。本研究的目的是探讨炎症相关microRNA在肌肉萎缩中的表达和作用。HPV16转基因小鼠发生全身性炎症和肌肉萎缩，是癌症恶病质的模型。我们使用来自这些小鼠的腓肠肌样本来研究microRNA的表达。然后使用生物信息学工具来探索它们在肌肉萎缩中的潜在作用。在研究的microRNA中，miR-223-3p（p=0.004），let-7b-5p(p=0.034)，miR-21a-5p（p=0.034），miR-150-5p（p=0.027），和miR-155-5p(p=0.011)在恶病质小鼠的肌肉中显著上调。电脑分析显示这些microRNAs参与了与肌肉消瘦相关的几个过程，包括肌肉结构发育和MAPK通路的调节。在分析蛋白质-蛋白质相互作用(PPI)网络时，获得了两个主要集群和前10个枢纽。从前10名，Kras（p=0.050）和Ccdn1（p=0.009）在恶病质肌肉中下调，以及Map2k3（p=0.007）。这些结果表明miR-223-3p,let-7b-5p，miR-21a-5p,miR-150-5p,还有miR-155-5p,在HPV16转基因小鼠的肌肉萎缩中起作用，可能通过调节MAPK级联。需要未来的实验研究来验证我们的计算机模拟分析，并探索这些microRNAs和MAPK信号作为癌症恶病质新的潜在生物标志物或治疗靶点的有效性。
