Obesity contributes to high cancer risk in humans and the mechanistic links between these two pathologies are not yet understood. Recent emerging evidence has associated obesity and cancer with metabolic abnormalities and inflammation where microRNA regulation has a strong implication. In this study, we have developed an integrated framework to unravel obesity-cancer linkage from a microRNA regulation perspective. Different from traditional means of identifying static microRNA targets based on sequence and structure properties, our approach focused on the discovery of context-dependent microRNA-mRNA interactions that are potentially associated with disease progression via large-scale genomic analysis. Specifically, a meta-regression analysis and the integration of multi-omics information from obesity and cancers were presented to investigate the microRNA regulation in a dynamic and systematic manner. Our analysis has identified a total number of 2,143 unique microRNA-gene interactions in obesity and seven types of cancer. Common interactions in obesity and obesity-associated cancers are found to regulate genes in key metabolic processes such as fatty acid and arachidonic acid metabolism and various signaling pathways related to cell growth and inflammation. Additionally, modulated co-regulations among microRNAs targeting the same functional processes were reflected through the analysis. We demonstrated the statistical modeling of microRNA-mediated gene regulation can facilitate the association study between obesity and cancer. The entire framework provides a powerful tool to understand multifaceted gene regulation in complex human diseases that can be generalized in other biomedical applications.

中文翻译：

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通过microRNA调控阐明肥胖与癌症之间的分子联系

肥胖会导致人类患癌症的风险增加，而这两种病理之间的机制联系尚不清楚。最近出现的证据表明，肥胖和癌症与代谢异常和炎症相关，其中microRNA调控具有重要意义。在这项研究中，我们已经开发出一个整合的框架，以从microRNA调控的角度揭示肥胖与癌症的联系。与基于序列和结构特性识别静态microRNA靶标的传统方法不同，我们的方法侧重于通过大规模基因组分析发现可能与疾病进展相关的上下文相关的microRNA-mRNA相互作用。特别，提出了荟萃回归分析和肥胖症和癌症的多组学信息的整合，以动态和系统的方式研究microRNA调控。我们的分析确定了肥胖症和七种癌症中总共2143种独特的microRNA基因相互作用。发现肥胖症和与肥胖症有关的癌症中的常见相互作用调节着关键代谢过程中的基因，例如脂肪酸和花生四烯酸代谢以及与细胞生长和炎症相关的各种信号通路。另外，通过分析反映了靶向相同功能过程的微小RNA之间的调节共调节。我们证明了microRNA介导的基因调控的统计模型可以促进肥胖与癌症之间的关联研究。