Zhang Luhan, Yu Hong, Deng Tian, Ling Li, Wen Juan, Lv Mingfen, Ou Rongying, Wang Qiaozhi, Xu Yunsheng
School of Basic Medicine, Southwest Medical University, Luzhou, China.
Department of Dermatovenerology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
Front Oncol. 2021 Dec 16;11:783868. doi: 10.3389/fonc.2021.783868. eCollection 2021.
Human papillomavirus (HPV)-mediated cervical carcinogenesis is a multistep progressing from persistent infection, precancerous lesion to cervical cancer (CCa). Although molecular alterations driven by viral oncoproteins are necessary in cervical carcinogenesis, the key regulators behind the multistep process remain not well understood. It is pivotal to identify the key genes involved in the process for early diagnosis and treatment of this disease. Here we analyzed the mRNA expression profiles in cervical samples including normal, cervical intraepithelial neoplasia (CIN), and CCa. A co-expression network was constructed using weighted gene co-expression network analysis (WGCNA) to reveal the crucial modules in the dynamic process from HPV infection to CCa development. Furthermore, the differentially expressed genes (DEGs) that could distinguish all stages of progression of CCa were screened. The key genes involved in HPV-CCa were identified. It was found that the genes involved in DNA replication/repair and cell cycle were upregulated in CIN compared with normal control, and sustained in CCa, accompanied by substantial metabolic shifts. We found that upregulated fibronectin type III domain-containing 3B (FNDC3B) and downregulated bisphosphoglycerate mutase (BPGM) could differentiate all stages of CCa progression. In patients with CCa, a higher expression of FNDC3B or lower expression of BPGM was closely correlated with a shorter overall survival (OS) and disease-free survival (DFS). A receiver operating characteristic (ROC) analysis of CIN and CCa showed that FNDC3B had the highest sensitivity and specificity for predicting CCa development. Taken together, the current data showed that FNDC3B and BPGM were key genes involved in HPV-mediated transformation from normal epithelium to precancerous lesions and CCa.
人乳头瘤病毒（HPV）介导的宫颈癌发生是一个多步骤过程，从持续性感染、癌前病变发展到宫颈癌（CCa）。虽然病毒癌蛋白驱动的分子改变在宫颈癌发生过程中是必要的，但多步骤过程背后的关键调节因子仍未得到充分了解。识别该过程中涉及的关键基因对于这种疾病的早期诊断和治疗至关重要。在此，我们分析了包括正常宫颈、宫颈上皮内瘤变（CIN）和CCa在内的宫颈样本中的mRNA表达谱。使用加权基因共表达网络分析（WGCNA）构建共表达网络，以揭示从HPV感染到CCa发展的动态过程中的关键模块。此外，筛选出可区分CCa进展所有阶段的差异表达基因（DEG）。确定了参与HPV-CCa的关键基因。研究发现，与正常对照相比，参与DNA复制/修复和细胞周期的基因在CIN中上调，并在CCa中持续存在，同时伴有大量代谢变化。我们发现上调的含III型纤连蛋白结构域3B（FNDC3B）和下调的二磷酸甘油酸变位酶（BPGM）可区分CCa进展的所有阶段。在CCa患者中，FNDC3B高表达或BPGM低表达与较短的总生存期（OS）和无病生存期（DFS）密切相关。对CIN和CCa的受试者工作特征（ROC）分析表明，FNDC3B对预测CCa发展具有最高的敏感性和特异性。综上所述,目前的数据表明FNDC3B和BPGM是参与HPV介导的从正常上皮向癌前病变和CCa转化的关键基因。
