Abstract
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.
Highlights
Cervical carcinoma (CCa) is the fourth most commonly diagnosed and fatal gynecological cancer in the world [1]
Based on the differential expression analysis and weighted gene co-expression network analysis (WGCNA) analysis of an integrated dynamic process from normal to cervical intraepithelial neoplasia (CIN), and cervical cancer (CCa), we found that fibronectin type III domain-containing 3B (FNDC3B) and bisphosphoglycerate mutase (BPGM) could differentiate all stages in a stepwise progression of CCa
To investigate the molecular alternations in stepwise progression of Human papillomavirus (HPV)-associated CCa, the GSE138080 dataset was downloaded from the Gene Expression Omnibus (GEO) database to analyze the mRNA expression profiles in cervical samples spanning from normal, CIN, to CCa
Summary
Cervical carcinoma (CCa) is the fourth most commonly diagnosed and fatal gynecological cancer in the world [1]. There were more than 600,000 new cases and 340,000 CCarelated deaths worldwide in 2020 [1]. In China, there were 106,400 new cases in 2018, approximately 34% of which are fatal [2, 3]. In the US, there were nearly 13,800 cases of invasive CCa and estimated 4,290 deaths of CCa in 2020 [4]. Human papillomavirus (HPV) infection is the major cause of the development of CIN and CCa [5,6,7]. HPV vaccine and early screening effectively reduce the incidence and mortality, the majority of CCa is diagnosed in advanced stages [8]. It is indispensable to identify novel biomarkers to predict the occurrence of CIN and CCa
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