Summary: Cervical cancer is a type of cancer that could affect women of all ages. Among other factors, the human papillomavirus (HPV) is a major cause of cervical cancer. In particular, HPV strains 16 and 18, which produce the oncoproteins E6 and E7, respectively, have been found to be involved in the development of cervical cancer. This article aims to discuss the roles of E6 and E7 oncoproteins in cervical cancer progression and their potential as therapeutic targets.
1. E6 Oncoprotein and Cervical Cancer
Several studies have shown that E6 oncoprotein is responsible for the inhibition of apoptosis, as well as cell-cycle regulation disruption. E6 binds to and directs the ubiquitination and subsequent degradation of tumor protein, p53. P53 functions to arrest the cell cycle when there is DNA damage. This control measure ensures that no further replication of the damaged DNA occurs. As a result of the downregulation of p53, infected cells are allowed to proliferate, which can lead to the formation of cervical tumors. Furthermore, proteins such as BAK and MDA-5 act as a countermeasure to the E6-induced increase in cell growth. It is important to note that the activity of E6 oncoprotein is crucial to tumorigenesis.
Another action of E6 oncoprotein involves the recruitment of telomerase, an enzyme that creates new chromosome ends. When normal cells replicate, the ends of chromosomes shrink. The process continues until the chromosomes are too short to handle the necessary number of divisions. In contrast, tumor cells never reach the crisis phase because they have very long telomeres. Telomerase is reactivated by E6 so that the cells may maintain infinite proliferation and ultimately give rise to cancerous tumors.
Targeted inhibition of E6 oncoprotein has been a major focus of cervical cancer research. The inhibition of E6 leads to the upregulation of p53 and an increase in apoptosis, representing a potential route for therapeutic intervention for cervical cancer.
2. E7 Oncoprotein and Cervical Cancer
Another oncoprotein, E7, is responsible for the transformation of cervical epithelial cells into malignancy by inhibiting the tumor suppressor, retinoblastoma protein (Rb). Rb controls the cell cycle at the G1 phase by restricting the progression to S phase. E7 targets Rb and destabilizes it, leading to unchecked proliferation and cellular transformation. A similar pathway is activated by HPV E7 binding to p130, another member of the Rb family.
E7 also interferes with the regulation of Notch gene expression in cervical cells. The Notch pathway has long been recognized as a critical pathway in cell fate determination and developmental differentiation. By modulating gene expression in this pathway, E7 oncoprotein ultimately leads to the accumulation of undifferentiated cells in cervical tumors. Furthermore, HPV E7 promotes resistance to chemotherapy by inactivating pro-apoptotic proteins such as Bad and Bax.
The most promising approach to targeting E7 involves the use of therapeutic vaccines. These vaccines target E7 protein specifically, inducing T-cell-mediated immune responses that can selectively eliminate virus-infected cells. Clinical trials have provided evidence that vaccination with E7 peptides could improve overall survival rates among women with advanced cervical cancers.
3. The Interaction between E6 and E7
While both E6 and E7 have unique actions, interaction between these two proteins facilitates the oncogenicity of the virus. It has been demonstrated that E6 can facilitate the ubiquitination of p53 by targeting p53 directly, and E7 increases p53 degradation through destabilizing Rb. Furthermore, p53 inhibition leads to a decrease in transcriptional repression by p53 on the E6 promoter, thus leading to an increase in protein levels in the cell. The interaction results in a viral immune escape, paving the way for persistent infection that eventually may cause cervical cancer progression.
The interaction between E6 and E7 also creates a disparity in the cell. The loss of one or more cellular pathways that control proliferation is a hallmark of cancer formation. For instance, it has been shown that E6 increases the expression of human telomerase reverse transcriptase (hTERT), which is responsible for maintaining telomeres in tumor cells. On the other hand, E7, although it has minimal effect on hTERT expression, inhibits the function of Rb, which ultimately contributes to uncontrolled cell growth. Taken together, both proteins contribute to cell proliferation, differentiation, and transformation via interaction with host-cell pathways.
Inhibition of the E6-E7 complex has shown a considerable therapeutic potential for HPV-associated cancers, including cervical cancer. Therapeutic approaches aiming at degrading either E6 or E7 proteins, or inhibiting their interaction, have become a research focus in recent years, with the hope of identifying novel therapeutic targets.
Conclusion:
Cervical cancer associated with E6 and E7 oncogenes has been established as a major global health problem. Understanding the roles of these two proteins in the development of cervical cancer could enable targeted development of effective treatments. While current therapies are based on chemotherapy or radiotherapy, the potential of E6 and E7 as therapeutic targets continues to offer promise. Targeting the specific functioning roles of the E6 and E7 oncoproteins in cervical cancer progression represents a promising new area for research to bring about alternative treatments that may be less invasive than current options.
Ultimately, this could increase the survival rates in patients with cervical cancer and provide physicians with an alternative to the traditional therapeutic measures that have been used as the first line of defense. Although new therapies based on E6 and E7 oncoproteins are still in the preclinical stage, they represent a significant opportunity for treating cervical cancer at its source now and in the future.