The role of HPV‑induced epigenetic changes in cervical carcinogenesis (Review)

Abstract

Cervical cancer is associated with infection by certain types of human papillomaviruses (HPVs), and this affects women worldwide. Despite the improvements in prevention and cure of HPV-induced cervical cancer, it remains the second most common type of cancer in women in the least developed regions of the world. Epigenetic modifications are stable long-term changes that occur in the DNA, and are part of a natural evolutionary process of necessary adaptations to the environment. They do not result in changes in the DNA sequence, but do affect gene expression and genomic stability. Epigenetic changes are important in several biological processes. The effects of the environment on gene expression can contribute to the development of numerous diseases. Epigenetic modifications may serve a critical role in cancer cells, by silencing tumor suppressor genes, activating oncogenes, and exacerbating defects in DNA repair mechanisms. Although cervical cancer is directly related to a persistent high-risk HPV infection, several epigenetic changes have been identified in both the viral DNA and the genome of the infected cells: DNA methylation, histone modification and gene silencing by non-coding RNAs, which initiate and sustain epigenetic changes. In the present review, recent advances in the role of epigenetic changes in cervical cancer are summarized.

Exploring Differentially Methylated Genes in Vulvar Squamous Cell Carcinoma

“…Since hyper-methylation of the promoters of regulatory genes is known to result in activation of oncogenes and inactivation of tumor suppressor genes, proportion of hyper-methylated genes tends to be higher in cancerous tissue compared to healthy tissues from the same anatomical site. This has been observed in both HPV-associated cancers, e.g., cervical SCC, and in HPV-independent cancers, e.g., oral and laryngeal SCC [ 45 , 46 ]. Studies on cervical SCC indicate that the HPV-oncoproteins E6 and E7 activate DNA methyltransferases, which promote the hyper-methylation of CpG-islands and silencing of host genes, including CDH1 , TP53 , RASSF1, and CDKN2A [ 45 ].…”

“…This has been observed in both HPV-associated cancers, e.g., cervical SCC, and in HPV-independent cancers, e.g., oral and laryngeal SCC [ 45 , 46 ]. Studies on cervical SCC indicate that the HPV-oncoproteins E6 and E7 activate DNA methyltransferases, which promote the hyper-methylation of CpG-islands and silencing of host genes, including CDH1 , TP53 , RASSF1, and CDKN2A [ 45 ]. It could be investigated whether the HPV-oncoproteins cause gene silencing in HPV-associated VSCCs using a similar mechanism.…”

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…Methylome analyses of HPV-positive cancers revealed differences in DNA methylation compared to matching normal tissue or HPV-negative tumors and transfection studies have confirmed that the E6 and E7 oncoproteins provoked hypermethylation tumor suppressor genes and hypomethylation of proto-oncogenes [ 31 , 32 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ]. Both these viral proteins have been shown to upregulate the expression of DNMT1.…”

“…The mechanism(s) by which HR-HPV provoke hypomethylation of the host genome remain enigmatic. In conclusion, HPV-mediated changes in DNA methylation affects the expression of several cellular genes and has been proven to stimulate cell proliferation, cell survival, adhesion and migration [ 32 , 114 ].…”

“…Upregulation and downregulation of cellular microRNAs have been observed. The microRNAs dysregulated in HPV-positive cervical cancers are involved in cell proliferation, cell survival, angiogenesis, invasion, and migration underscoring their role in HR-HPV pathogenesis ( Table 3 ; [ 108 , 109 , 114 , 245 , 282 ]).…”