by Talia Gabay
Cervical cancer is the fourth most common cancer globally. This is largely attributed to the oncoproteins E6 and E7, which are produced by the body following infection and integration into the human DNA by a high-risk strain of the Human Papillomavirus (HPV). These oncoproteins, can lead to tumour formation and progression,and are therefore considered viral bullies that wreak havoc in our bodies and ultimately cause issues where there would otherwise not be any. A tremendous amount of research has been conducted on the role of these oncoproteins and data points to their course of action in cervical cancer development. Like looking at a connect the dots picture, each dot symbolizes a protein interaction, pathway modulation or function that E6 and E7 are involved in to drive cervical cancer progression. To make sense of how these proteins initiate and maintain the cancerous phenotype, the dots must be connected. This review by Vats et al. aims to do just that.
The authors firstly highlight the known biochemical interactions between cellular proteins in an attempt to make connections between the various processes. However, this also identified the critical information about E6 and E7 that remains elusive. Cell cycle dysregulation, epigenetics, cancer maintenance, telomerase activation and involvement in all hallmarks of cancer were amongst the key processes discussed by this review to illustrate what is known about the regulatory role of E6 and E7. Indeed, these proteins disrupt cellular normality, leading to the development and maintenance of malignant cervical lesions. However, as a biochemical process is uncovered, its significance or contribution to tumour formation must then be determined. It is not only about which process is occurring but also where, how and why it is happening that is significant. It is interesting how the gaps link back to the viral life cycle and how E6 and E7 activate processes that are not needed by this cycle directly but drive tumorigenesis. Could this result from off-target mistakes? It seems that the closer we look the less we see. However, the more we know about the functionality of E6 and E7, the better equipped we will be to provide the information needed to treat and even prevent cervical cancer by disrupting the protein sidekicks that allow E6 and E7 to carry out their mission of malignant transformation.
Figure 1: An illustration of what is known and still remains elusive about the rosed E6 and E7 play in cervical cancer. This image combined figures from both Mittal and Banks as well as Vats et al to produce the overall map of the processes each oncoprotein is involved in, what they both are involved in, as well as what remains unknown. All that is unknown is illustrated in a red box. If the viral life cycle is involved, this is further highlighted red. Yellow usually means that it is related to E6 alone. Purple usually means it relates to E7 alone. However, both E6 and E7 are involved in interferon signaling. Red question marks mean the links have yet to be made or that there are gaps in our knowledge.
Mittal, S. & Banks, L. 2017. Molecular mechanisms underlying human papillomavirus E6 and E7 oncoprotein-induced cell transformation. Mutation Research/Reviews in Mutation Research. 772:23-35. DOI: 10.1016/j.mrrev.2016.08.001.
Vats, A., Trejo-Cerro, O., Thomas, M. & Banks, L. (2021). Human papillomavirus E6 and E7: What remains? Tumour Virus Research. 11:200213. DOI: 10.1016/j.tvr.2021.200213.