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Abstract：
Head and neck squamous cell carcinoma (HNSC) is one of most common malignancies with high mortality worldwide. Importantly, the molecular heterogeneity of HNSC complicates the clinical diagnosis and treatment, leading to poor overall survival outcomes. To dissect the complex heterogeneity, recent studies have reported multiple molecular subtyping systems. For instance, HNSC can be subdivided to four distinct molecular subtypes: atypical, basal, classical, and mesenchymal, of which the mesenchymal subtype is characterized by upregulated epithelial-mesenchymal transition (EMT) and associated with poorer survival outcomes. Despite a wealth of studies into the complex molecular heterogeneity, the regulatory mechanism specific to this aggressive subtype remain largely unclear. Herein, we developed a network-based bioinformatics framework that integrates lncRNA and mRNA expression profiles to elucidate the subtype-specific regulatory mechanisms. Applying the framework to HNSC, we identified a clinically relevant lncRNA LNCOG as a key master regulator mediating EMT underlying the mesenchymal subtype. Five genes with strong prognostic values, namely ANXA5, ITGA5, CCBE1, P4HA2, and EPHX3, were predicted to be the putative targets of LNCOG and subsequently validated in other independent datasets. By integrative analysis of the miRNA expression profiles, we found that LNCOG may act as a ceRNA to sponge miR-148a-3p thereby upregulating ITGA5 to promote HNSC progression. Furthermore, our drug sensitivity analysis demonstrated that the five putative targets of LNCOG were also predictive of the sensitivities of multiple FDA-approved drugs. In summary, our bioinformatics framework facilitates the dissection of cancer subtype-specific lncRNA regulatory mechanisms, providing potential novel biomarkers for more optimized treatment of HNSC.
摘要：
头颈部鳞状细胞癌（HNSC）是全球最常见的恶性肿瘤之一，死亡率高。重要的是,HNSC的分子异质性使临床诊断和治疗复杂化,导致整体生存结果不佳。为了剖析复杂的异质性，最近的研究报道了多个分子亚型系统。例如,HNSC可以细分为四种不同的分子亚型：非典型，基底,古典,和间充质，其中间充质亚型的特征是上皮-间充质转化（EMT）上调，并与较差的生存结局相关。尽管对复杂的分子异质性进行了大量研究，这种侵袭性亚型特有的调节机制仍不清楚.在这里，我们开发了一个基于网络的生物信息学框架,该框架整合了lncRNA和mRNA表达谱,以阐明亚型特异性调控机制.将框架应用于HNSC，我们确定了临床相关的lncRNALNCOG作为介导间充质亚型基础EMT的关键主调节因子.5个具有强预后价值的基因，即ANXA5，ITGA5，CCBE1，P4HA2和EPHX3被预测为LNCOG的假定目标，随后在其他独立数据集中进行了验证。通过对miRNA表达谱的综合分析，我们发现LNCOG可能作为ceRNA来海绵miR-148a-3p,从而上调ITGA5以促进HNSC进展.此外，我们的药物敏感性分析表明,LNCOG的5个推定目标也可预测多种FDA批准药物的敏感性.总之,我们的生物信息学框架促进了癌症亚型特异性lncRNA调控机制的解剖，为HNSC的更优化治疗提供潜在的新型生物标志物。
