Human papillomavirus and molecular considerations for cancer risk

Abstract

Human papillomaviruses (HPVs) are a major cause of cancer globally, including cervical cancer. The HPV 'early' proteins, E6 and E7, are the chief oncoproteins involved in cancer progression. These oncoproteins are more highly expressed in high-grade dysplasias and invasive cancer coincident with reduced viral DNA replication and reduced production of infective progeny virions. The E6 and E7 oncoproteins interact with several cellular proteins-classically TP53 and RB1, respectively-leading to the degradation of several of these proteins, although all interactions do not necessarily result in the degradation of a cellular protein.HPV infection is also associated with viral and host DNA methylation changes, many of which also occur in cancer types not associated with HPV infection. The E6 and E7 interactions with cellular proteins and DNA methylation changes are associated with changes in the integrity of key cellular pathways that regulate genomic integrity, cell adhesion, the immune response, apoptosis, and cell cycle control. The alterations in key cellular pathways may provide useful biomarkers to improve the sensitivity of current cancer screening methods, such as the Papanicolaou test. This review provides a detailed summary of the interactions of E6 and E7 with cellular proteins and alterations in cellular DNA methylation associated with HPV infection. The importance of molecular biomarkers to the clinical setting, underserved populations, and general public health is discussed.

Viral epigenomes in human tumorigenesis

“…HPVs are currently believed to be the most common cause of cancers induced by an infectious agent (zur Hausen, 2006(zur Hausen, , 2009Whiteside et al, 2008). HPVs are a group of viruses of the Papillomaviridae family, which contain double-stranded circular DNA of B8 kb (Table 1) and use the host DNA machinery to replicate and proliferate.…”

“…Several recent studies have shown that E6 and E7 bind to different cell proteins involved in the processes of adhesion, apoptosis, cell cycle, DNA repair, metabolism, signal transduction, transcription and other functions (Horikawa and Barrett, 2003;Whiteside et al, 2008;Howie et al, 2009;McLaughlin-Drubin and Mu¨nger, 2009). In addition, deregulation of the expression of several miRNAs in the host cells associated with HPV infection induced by some of its oncoproteins has been noted by several authors (Martinez et al, 2008;Reshmi and Pillai, 2008;Wang et al, 2008Wang et al, , 2009.…”

“…In fact, DNA methylation in host cell genes has been investigated as a potential biomarker for early detection of cervical cancer by extensive screening of premalignant and invasive cervical carcinoma samples (Lai et al, 2008;Whiteside et al, 2008;Fernandez et al, 2009;Ferrari et al, 2009;Wentzensen et al, 2009).…”

Identification of Frequent Promoter Methylation of Death-Associated Protein Kinase in Liquid-Based Papanicolaous Test Samples in Vietnamese Population

“…Notably, promoter hypermethylation of DAPK was investigated and found to be significant higher in high-risk HPV infected samples than low-risk HPV infected samples and non-HPV infected samples (p<0.0001). It is thought that some Oncogenic viruses are known to interact with, and to modulate the expression of DNA methyltransferases (DNMTs), resulting to in the transactivation and transrepression of both cellular and viral genes [23,24]. Even though the relationship between HPV and aberrant methylation in CC is not well understood, some reports suggested E6 and E7 oncoprotein of high-risk HPV increase the expression and activity of DNMT1, which is the major mammalian enzyme responsible for maintaining CpG methylation patterns in the cell following replication, through the suppression of TSG p53 [25,26].…”

Immunohistochemistry in the Diagnosis of Squamous Intraepithelial Lesions of the Uterine Cervix

“…The paradox is that, although infection with oncogenic types of HPV is very common, malignancy is a rare outcome. This difference in incidence between infection and cancer development reveals the significance of complex interactions between viral, environmental and host-related factors (Frazer, 2009;Moscicki et al, 2006;Snijders et al, 2006;Whiteside et al, 2008;zur Hausen, 2008). Viral persistence is an important determinant in this sequence of events, while immune status, viral integration into the host DNA, and infection with multiple HPV genotypes have significant roles.…”