Cervical cancer has remained the most prevalent and lethal malignancy among women worldwide and accounted for over 250,000 deaths in 2019. Nearly ninety-five per cent of cervical cancer cases are associated with persistent infection with high-risk Human Papillomavirus (HPV), and seventy per cent of these are associated with viral integration in the host genome. HPV-infection imparts specific changes in the regulatory network of infected cancer cells that are of diagnostic, prognostic and therapeutic importance. Here, we conducted a systems-level analysis of the regulatory network changes, and the associated regulatory proteins thereof, in HPV-positive cervical cancer. We applied functional pathway analysis to show that HPV-positive cancers are characterised by perturbations of numerous cellular processes, predominantly in those linked to the cell cycle, mitosis, cytokine and immune cell signalling. Using computational predictions, we revealed that HPV-positive cervical cancers are regulated by transcription factors including, SOX2, E2F, NANOG, OCT4, and MYC, which control various processes such as the renewal of cancer stem cells, and the proliferation and differentiation of tumour cells. Through the analysis of upstream regulatory kinases, we identified the mitogen-activated protein kinases; among others, MAPK1, MAPK3 and MAPK8, and the cyclin-dependent kinases; among others, CDK1, CDK2 and CD4, as the key kinases that control the biological processes in HPV-positive cervical cancers. Taken together, we uncover a landscape of the key regulatory pathways and proteins in HPV-positive cervical cancers, all of which may provide attractive drug targets for future therapeutics.

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系统方法确定HPV阳性宫颈癌的关键调控因子

宫颈癌仍然是全球女性中最普遍和致命的恶性肿瘤，2019年导致25万多例死亡。将近95％的宫颈癌病例与高危型人乳头瘤病毒（HPV）持续感染有关，每例70％其中有百分之一与宿主基因组中的病毒整合有关。HPV感染使受感染癌细胞的调控网络发生特定变化，这具有诊断，预后和治疗重要性。在这里，我们对HPV阳性宫颈癌的调节网络变化及其相关的调节蛋白进行了系统级分析。我们应用功能途径分析表明，HPV阳性癌症的特征是许多细胞过程受到干扰，主要与细胞周期，有丝分裂，细胞因子和免疫细胞信号传导有关。使用计算预测，我们发现HPV阳性子宫颈癌受转录因子（包括SOX2，E2F，NANOG，OCT4和MYC）调控，这些转录因子控制着各种过程，例如癌症干细胞的更新以及肿瘤的增殖和分化。细胞。通过分析上游调节激酶，我们确定了促分裂原活化的蛋白激酶。其中，MAPK1，MAPK3和MAPK8以及细胞周期蛋白依赖性激酶；其中，CDK1，CDK2和CD4是控制HPV阳性宫颈癌生物学过程的关键激酶。综上所述，我们发现了HPV阳性宫颈癌的关键调控途径和蛋白质，