Human papilloma virus, DNA methylation and microRNA expression in cervical cancer (Review)

Abstract

Cancer is a complex disease caused by genetic and epigenetic abnormalities that affect gene expression. The progression from precursor lesions to invasive cervical cancer is influenced by persistent human papilloma virus (HPV) infection, which induces changes in the host genome and epigenome. Epigenetic alterations, such as aberrant miRNA expression and changes in DNA methylation status, favor the expression of oncogenes and the silencing of tumor-suppressor genes. Given that some miRNA genes can be regulated through epigenetic mechanisms, it has been proposed that alterations in the methylation status of miRNA promoters could be the driving mechanism behind their aberrant expression in cervical cancer. For these reasons, we assessed the relationship among HPV infection, cellular DNA methylation and miRNA expression. We conclude that alterations in the methylation status of protein-coding genes and various miRNA genes are influenced by HPV infection, the viral genotype, the physical state of the viral DNA, and viral oncogenic risk. Furthermore, HPV induces deregulation of miRNA expression, particularly at loci near fragile sites. This deregulation occurs through the E6 and E7 proteins, which target miRNA transcription factors such as p53.

Figure 1

Regulation of viral and cellular gene methylation by the E6 and E7 oncoproteins of HR-HPV. Integration of viral DNA into the cellular genome causes genetic and epigenetic alterations. The E6 and E7 oncoproteins of HR-HPV increase the expression and activity of DNA methyltransferases, particularly DNMT1. (A) Binding of p53 to Sp1 (p53/Sp1) forms a repressor complex for DNMT1 transcription. Degradation of p53 by E6 avoids the formation of this repressor complex and Sp1 induces the expression and activity of DNMT1. (B) E2F positively regulates the promoter activity of DNMT1. Binding of E7 to pRb (E7/pRb) causes the release of E2F, favoring the expression of DNMT1. Binding of E7 to DNMT1 (E7/DNMT1) induces a conformational change in DNMT1, exposing its DNA binding site and promoting DNA binding; once the E7/DNMT1 complex binds DNA, DNMT1 closes on the DNA and maintains a stable DNMT1/DNA interaction, and E7 dissociates from the complex. Overexpression of DNMT1 results in hypermethylation of tumor-suppressor gene promoters, which leads to cellular transformation and tumorigenesis. HR-HPV, high-risk HPV; DNMT, DNA methyltransferase.