头颈部鳞状细胞癌（HNSCC）是全球最常见的癌症之一，每年导致数十万人死亡。不幸的是，多数患者在晚期被诊断，只有一部分对治疗有良好的反应。为填补该空白，我们提出了一项回顾性的计算模拟研究，以揭示导致HNSCC发展的基因-miRNA相互作用。此外，通过识别拓扑生物标志物作为设计新药的来源。为了实现这一目标，我们全面重新评估了患者和对照组的基因和miRNA基因型，采用蛋白质相互作用（PPI）和二部图miRNA靶标网络。细胞骨架重塑、细胞外基质（ECM）、免疫系统、蛋白酶解和能量代谢已被确定为参与HNSCC发病机制的主要功能模块。值得注意的是，我们的研究结果显示了一个协同的分子作用景观，激活细胞周期和增殖促进基因的同时，失活那些抑制基因。在这种情况下，诸如VEGFA、EMP1、PPL、KRAS、MET、TP53、MMPs和HOXs等基因，以及mir-6728和mir-99a等miRNA，被确定为推动HNSCC肿瘤发生的关键因子。尽管这些HNSCC亚型具有异质性，以及存在依赖背景关系的相关研究的局限性，但与先前发表的研究结果的重叠是令人鼓舞的。因此，它支持进一步研究与HNSCC相关的关键分子，无论是已有关联还是未有关联的。

Head and neck squamous cell carcinoma (HNSCC) is among the most common cancer worldwide, accounting for hundreds thousands deaths annually. Unfortunately, most patients are diagnosed in an advanced stage and only a percentage respond favorably to therapies. To help fill this gap, we hereby propose a retrospective in silico study to shed light on gene-miRNA interactions driving the development of HNSCC. Moreover, to identify topological biomarkers as a source for designing new drugs. To achieve this, gene and miRNA profiles from patients and controls are holistically reevaluated using protein-protein interaction (PPI) and bipartite miRNA-target networks. Cytoskeletal remodeling, extracellular matrix (ECM), immune system, proteolysis, and energy metabolism have emerged as major functional modules involved in the pathogenesis of HNSCC. Of note, the landscape of our findings depicts a concerted molecular action in activating genes promoting cell cycle and proliferation, and inactivating those suppressive. In this scenario, genes, including VEGFA, EMP1, PPL, KRAS, MET, TP53, MMPs and HOXs, and miRNAs, including mir-6728 and mir-99a, emerge as key players in the molecular interactions driving HNSCC tumorigenesis. Despite the heterogeneity characterizing these HNSCC subtypes, and the limitations of a study pointing to relationships that could be context dependent, the overlap with previously published studies is encouraging. Hence, it supports further investigation for key molecules, both those already and not correlated to HNSCC.