Involvement of Human Papillomaviruses in Cervical Cancer

Abstract

Human papillomaviruses (HPV) are the first viruses to have been acknowledged to prompt carcinogenesis, and they are linked with cancers of the uterine cervix, anogenital tumors, and head and neck malignancies. This paper examines the structure and primary genomic attributes of HPV and highlights the clinical participation of the primary HPV serotypes, focusing on the roles that HPV-16 and 18 play in carcinogenesis. The mechanisms that take place in the progression of cervical neoplasia are described. The oncogenic proteins E6 and E7 disrupt control of the cell cycle by their communication with p53 and retinoblastoma protein. Epidemiological factors, diagnostic tools, and management of the disease are examined in this manuscript, as are the vaccines currently marketed to protect against viral infection. We offer insights into ongoing research on the roles that oxidative stress and microRNAs play in cervical carcinogenesis since such studies may lead to novel methods of diagnosis and treatment. Several of these topics are surfacing as being critical for future study. One particular area of importance is the study of the mechanisms involved in the modulation of infection and cancer development at cervical sites. HPV-induced cancers may be vulnerable to immune therapy, offering the chance to treat advanced cervical disease. We propose that oxidative stress, mRNA, and the mechanisms of HPV infection will be critical points for HPV cancer research over the next decade.

Keywords: HPV genotype; HPV vaccine; HPV-induced carcinogenesis; cervical cancer; human papillomaviruses.

FIGURE 1

HPV classification based on the nucleotide sequence of the capsid protein L1 gene (Burd, 2016).

FIGURE 2

Prevalence of high-risk HPV infection among females undergoing cervical screening. HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial (Kitchener et al., 2006). Compiled using information from Kitchener et al. (2006).

FIGURE 3

Human papillomavirus (HPV) life cycle and cancer. Cartoon depicting normal stratified cervical epithelium (left), HPV-infected epithelium (center), and HPV-induced cancer (right). Epithelial layers are indicated on the far left, and HPV life cycle stages are indicated on the far right. Episomal genomes are shown as orange circles and integrated genomes are shown as orange stripes. (Left) Normal keratinocyte differentiation: basal cells divide and daughter cells migrate upward, beginning the differentiation process. As differentiation proceeds, cells exit the cell cycle. Fully keratinized squames slough off from the apical surface. (Middle) Productive HPV infection: HPV virions gain access to basal cells via microwounds. The viral genomes migrate to the nucleus, where they are maintained at ˜100 copies/cell. As daughter cells begin differentiation, viral genomes are amplified. Cell nuclei are retained and chromatin is activated to support viral DNA replication. (Right) Cancer: viral genomes often integrate into the host genome and E6/E7 expression is increased, leading to enhanced proliferation and the accumulation of cellular mutations. Cellular differentiation is lost, and cancerous cells invade into the dermal layer as well as into neighboring tissues (Langsfeld and Laimin, 2016).

FIGURE 4

Schematic model of HPV-driven carcinogenesis. (A) A multistep molecular mechanism of host-viral interaction (Senapati et al., 2016). The initial outcome of carcinogenesis is modulated by both viral (high-risk versus low-risk HPV types, HPV integration) and host factors (inflammatory response, oxidative stress). Inflammatory response upon initial infection such as IFN response plays role in reducing episomal HPV resulting clearance of infection. Integration of HPV is (initiated with DNA damage. The IFN induced loss of episomal HPV and down-regulation of E2 leads to the selection of cells with integrated HPV genomes expressing higher levels of E6 and E7. Once the early genes E6 and E7 are expressed, TLR9 down regulated and IFN response impaired, resulting a conducive milieu for immune evasion and persistent infection. Up regulation of E6/E7 increases genetic instability and chromosomal rearrangements that increase the risk of integration. Overexpression of E6/E7 leads to deregulation of the cell cycle via p53 and Rb degradation, deregulation of oncogenes and miRNAs expression. Epigenetic and genetic modification in viral and host genome leads to the deregulation of E6 and E7 oncogenes, and host tumor suppressor genes that lead to carcinogenesis. Oxidative modification of TFs also leads to altered gene expression and carcinogenesis. (B) Schematic model of the interaction between microRNAs and factors involved in malignant transformation caused by HPVE6 and E7 expression in cervical cancer cell (del Mar Diaz-Gonzalez et al., 2015). E6 disrupts the expression of miR-23b, miR-218, and miR-34a via p53 degradation and their expression is transactivated by the binding of p53 to consensus sites in the promoter regions, affecting the expression of cell cycle regulators, such as E2, cyclin D1, CDK4, CDK6, E2F1, E2F3, E2F5, Bcl-2, SIRT1, p18, uPA, and LAMBD3. In the overexpression of miR-15/16 cluster byE7, E2F1 transactivates the c-Myb expression and represses the c-Myc expression, and then the microRNA cluster regulation is controlled by binding of c-Myc or c-Myb to promoter region of microRNA cluster. The increased expression of miR-15a/miR-16-1 induces the inhibition of cell proliferation, survival, and invasion. The down regulation of miR-203 by E7 is mediated by MAPK/PKC pathway.)