Human Papillomavirus (HPV) is a common DNA virus that can infect skin and mucous membranes. While many HPV infections are temporary, certain types, known as high-risk HPV, can lead to cancer. The virus achieves this by producing specific proteins, primarily E6 and E7, which interfere with normal cell functions.
Functions of HPV E6
The HPV E6 protein disrupts the normal regulation of cell growth and death. Its primary mechanism involves targeting the tumor suppressor protein p53 for degradation. E6 forms a complex with p53 and a cellular enzyme called E6-Associated Protein (E6-AP), which tags p53 for destruction by the cell’s proteasome system.
P53 normally acts to prevent cell growth and promotes programmed cell death (apoptosis) in the presence of DNA damage. By eliminating p53, E6 allows cells with damaged DNA to continue dividing without proper control, thereby creating an environment conducive to viral replication and cell survival. Beyond p53, E6 interacts with other cellular proteins, including Bak, which initiates apoptosis, and components that regulate cell cycle progression.
Functions of HPV E7
Similar to E6, the HPV E7 protein also targets a key tumor suppressor, the retinoblastoma protein (Rb). High-risk HPV E7 binds to Rb, leading to its degradation through the ubiquitin pathway. Rb typically acts as a brake on the cell cycle, preventing cells from dividing uncontrollably by regulating transcription factors like E2F.
When E7 inactivates Rb, E2F transcription factors are released, promoting the expression of genes necessary for cell cycle progression and DNA replication. This interference with cell cycle checkpoints results in uncontrolled cell proliferation, benefiting the virus by providing a cellular environment suitable for its own replication. E7 also targets other proteins, including p107 and p130, members of the Rb family, and affects cyclin-dependent kinase inhibitors.
How E6 and E7 Drive Cancer Progression
The combined and sustained expression of E6 and E7 from high-risk HPV types is a significant factor in cellular immortalization and malignant transformation. While a transient HPV infection often clears naturally, persistent infection with high-risk types, such as HPV16 and HPV18, allows E6 and E7 to continuously disrupt cellular regulatory pathways. This ongoing interference with p53 and Rb leads to a loss of cell cycle control, promoting unchecked cell division.
Their synergistic actions result in genomic instability, where cells accumulate mutations and chromosomal abnormalities. E6 and E7 also contribute to the evasion of immune surveillance, which allows infected cells to escape detection and destruction by the body’s immune system. The continuous expression of these oncoproteins is necessary for maintaining the cancerous state, driving genetic changes that lead to the development of cervical cancer and other HPV-related malignancies.
E6 and E7 as Therapeutic and Diagnostic Targets
The consistent presence and activity of E6 and E7 in high-risk HPV-associated cancers make them valuable targets for diagnostic and therapeutic strategies. Detecting the messenger RNA (mRNA) of E6 and E7 serves as a biomarker for high-risk HPV infection and helps assess the risk of cervical cancer development. This is particularly useful in screening programs, where E6/E7 mRNA testing offers greater specificity for disease diagnosis compared to simply detecting HPV DNA.
In the therapeutic landscape, E6 and E7 are attractive targets for novel cancer treatments because they are consistently expressed in tumor cells and are not found in healthy tissues. Research explores therapeutic vaccines designed to elicit an immune response against these viral proteins, aiming to target and eliminate HPV-infected cancer cells. Other approaches include small molecule inhibitors and gene editing techniques that aim to suppress E6 and E7 activity, thereby halting tumor growth and inducing cancer cell death.