The effect of human papillomavirus on p53 and pRb in relation to cervical cancer Lance Good PDBio 325 – Tissue Biology Fall 2018 Abstract Cervical cancer is one of the most common cancers among women throughout the world

The effect of human papillomavirus on p53 and pRb in relation to cervical cancer
Lance Good
PDBio 325 – Tissue Biology
Fall 2018

Abstract
Cervical cancer is one of the most common cancers among women throughout the world. Often cervical cancer originates from high-risk types of human papillomavirus variants, a sexually transmitted disease, infecting normal cells through small lesions in the cervix. When the cells proliferate to heal the lesion, proteins from HPV are introduced to the cells around the outer portion of the cervix or to the cells lining the cervical canal. These proteins are able to target different proteins and genes that regulate the cell cycle, causing deregulation of the cell cycle. With deregulation, cancerous cells are able to reproduce, leading to cancerous growths such as tumors. The cancer can turn metastatic, leave the cervix, and migrate to different areas in the body and metastasize, spreading the cancer from the original site. In recent years, vaccines have been introduced to protect against many different types of HPV that are high-risk and lead to cervical cancer but are not effective against all variants of HPV.

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Introduction
Cancer occurs across a wide variety of tissues in the human body and according to a recent study in Iran, will affect about 25% of the population by 2035, though these numbers will vary with quality of living and access to medical treatment (Iran Cancer Statistics). Cancer originates when cell cycle regulation is interrupted, allowing uncontrolled cell growth in tissues. This interruption is often caused by external sources such as HPV, known carcinogens, and exposure to certain elements such as UV light for extended periods of time. With continual growth of cells, tumors can form and can also spread throughout other tissues/organs in the body leading to a more intense cancer in a patient.
Among women, cervical cancer is one of the most common cancers (ESTIMATES OF). When dealing with cervical cancer, there are two variations, a squamous cell carcinoma type, and an adenocarcinoma type. While both of these cancers affect the cervix, they originate in different locations; squamous cell carcinomas begin in the stratified squamous epithelium of the outer portion of the cervix while adenocarcinomas begin in the columnar glandular cells lining the inner canal of the cervix, leading to the uterus. In the cervix, as well as other tissues, squamous cell carcinomas are more common (SPONTANEOUS).

Human Papillomavirus (HPV)
Human papillomavirus has many variations, from regular growths on skin such as warts, low-risk types of HPV that can lead to genital warts, and high-risk types that can lead to cancers in both males and females, primarily in the anal and penile regions for men, and in the anal, cervical, and vaginal regions for women. As the low-risk types and high-risk types can be attributed to sexual contact, they are considered to be STI’s. HPV infects the host through lesions of any sort; these lesions allow the virus to travel to the basement membrane where it will spread as the wound heals (Initial Steps). The viral proteins are few, with the most important being E1 a viral helicase, allowing the virus to replicate, E6, a protein that induces the cell cycle, and E7, a protein that blocks regulation of a cell cycle checkpoint. The HPV virus is very common, but the severity and results of the infection depends on the type of HPV virus.

HPV in relation to Cervical Cancer
HPV is the most common means of cervical cancer developing (INTEGRATED), yet not all individuals who have contracted HPV will develop cervical cancer, due to the multiple types of HPV and their levels of risk. Those with high-risk HPV types will be the most likely to develop into cervical cancer. The HPV Type 16 and Type 18 variations are the most common high-risk variations with Type 16 HPV as the most common (INTEGRATED and HIGH RISK). Though HPV is closely related to cervical cancer, there are other factors that can lead to its development. These factors include many sexual partners, increasing the chances of other STI’s, and a weakened immune system. The immune system is a vital tool to combat the HPV virus, as it uses the innate portion of the immune system to eliminate the virus as early as possible (ROLE OF INNATE – PEER REVIEW!!).
Due to the nature of the HPV virus and the E6 and E7 proteins specifically, the normal cell cycle is disrupted, which leaves cell division unregulated. In a healthy cell, the cell cycle is composed of four different phases, G1, S, G2, and M. Between these phases, there are checkpoints that ensure that the cell is performing properly, otherwise cell division will stop and the cycle won’t complete. In a cancerous cell however, some proteins involved with these cycles and the checkpoints are mutated, allowing the cancerous cells to replicate even faster. Often, the proteins targeted are tumor suppressor genes and proteins such as TP53 and pRb. These proteins are important in the cell cycle regulation and when mutated, often lead to the formation of cancerous growths in the tissues they are found in.

Tumor Protein 53 (p53)
The TP53 gene is a tumor suppressor gene and codes for protein production that regulates part of the cell cycle. It’s protein, p53 does so by ensuring that cells do not divide when the developing cell is damaged. In a healthy cell, p53 is found in the nucleus where it “reads” DNA to check for errors. When the cells face destruction from chemicals, UV light, or cellular mutations, the p53 protein determines whether or not the cell can be repaired or if it should undergo apoptosis so that the damaged cell doesn’t divide and spread. This ensures that all cells that divide will not be damaged. Without the TP53 gene and p53, a portion of cell cycle regulation is lost, and the integrity of cellular reproduction is compromised, making the proliferation of cancerous cells more likely.

The Retinoblastoma Protein
Also a tumor suppressing protein, the retinoblastoma protein (pRb) also regulates a portion of the cell cycle, including the transition from the G1 phase to the S phase. This happens primarily through the protein forming a complex with the E2F-1 transcription factor, inactivating its function. This particular transcription factor engages the transition from G1 to S, but when the complex is formed with pRb, the cell cycle is unable to proceed (ROLE OF HPV). When the conditions within the cell are ready to continue with the cell cycle, pRb releases from the E2F-1 transcription factor, allowing the process to proceed. Unlike the TP53 gene which prevents the cell cycle from progressing when the developing cell is damaged, the pRb protein prevents the cell cycle from progressing until the conditions are right in the cell. Along with regulating the timing of the transition between two phases, pRb is also able to modify certain structures of the genome such as histones and chromatin so that the proper conditions for the cell can be met (ROLE OF PRB). Though the p53 and pRb have different purposes, they have the same function; to regulate the cell cycle so healthy cells are able to be produced.

HPV in Relation to TP53 and pRb
HPV proteins E6 and E7 are primarily responsible for cervical cancer formation due to their interactions with TP53 and pRb. E6 interacts with the TP53 protein while E7 interacts with the pRb protein. Since both proteins have unique roles in the cell cycle, E6 and E7 engage with the two cellular components in unique ways as well. Both of the HPV proteins interact with the different cellular components and change the function from normal to abnormal, creating issues for the tissues in which they are found; in this case, the cervix.
In a healthy cell, p53 regulates the integrity of reproducing cells, maintaining the proper function of the cell and the tissues that it composes. For p53, this proper function is to prevent the formation of tumors by regulating the cell cycle. However, once the HPV E6 protein forms a complex with it, the function of the protein is inhibited, leaving the reproducing cervical cells more prone to the chance of developing into cancerous cells. The HPV E6 protein forms doesn’t only form a complex with the gene, it also forms a complex with the E6-AP enzyme. Together the E6 and E6-AP work together to mark the p53 protein for degradation through other cellular components (THE ROLE OF HPV). With this important regulatory protein missing, the cell doesn’t have its full capacity to regulate the cell cycle, leaving the cervix prone to formation of cancerous cells. p53 isn’t only targeted in cervical cancer, in more than 50% of human cancers, mutations of this gene are present, indicating that it plays an important role in regulation of the cell cycle (Cellular Gatekeeper).
Just as the HPV E6 protein interacts with p53 to suppress the cell cycle, the HPV E7 protein interacts with pRb to further enable cancerous cell to proliferate, leading to the development of cancer in the cervix. Previous to the binding of E7 with pRb, pRb is bound to the transcription factor E2F-1, halting the cycle, a regulatory measure until the cellular conditions will yield a healthy cell that is able to create healthy daughter cells. HPV E7 then binds to pRb, breaking the bond between it and the transcription factor, thereby activating E2F-1. Once active, the cell cycle is able to move forward, even if the cellular components are not ready. This interaction provides another way for HPV to deregulate the cell cycle, allowing cancerous cells to proliferate and form cancerous growths in the cervix. Through two proteins, E6 and E7, high-risk HPV types are able to alter two important regulators of the cell cycle and lead to the formation of cancer.

Cervical Cancer Metastasis
Though the cancer forms in the tissues of the cervix, it spreads easily to other tissues in the body through a process called epithelial to mesenchymal transition or EMT (EMT IN CERVICAL). This process details the ability of cancerous cells to transition to different areas in the body through a conversion from an epithelial cell to a mesenchymal cell (REVIEW!!-Epithelial-Mesenchymal). This process is made possible through the snail transcription factor which promotes the EMT process. There are three different variations of EMT, but in regard to cancer metastasis, type three is the most common. After the differentiation into the mesenchymal cells, these cells have lost much of their polarity and are able to break through the basement membrane and enter the connective tissues, lymph nodes, and blood vessels. This cellular migration provides a means by which the mesenchymal cells are able to enter different tissues such as the bladder, liver or lungs and metastasize in them (EMT IN CERVICAL). While metastasis in organs farther from the cervix are possible, the more likely places for cervical cancer to spread are the uterus, fallopian tubes, vagina, and ovaries. Though early stages of cervical cancer may not affect fertility, later stages that have metastasized in the female reproductive system may require a hysterectomy to remove the cancerous tissues, leaving the individual unable to bear children.

Preventative Action – Gardasil 9
The immune system is composed of two portions, the innate immune system and the adaptive immune system. The innate immune system uses receptors to recognize foreign antigen and dispose of it, while the adaptive immune system needs to encounter the foreign antigen first, after which it will recognize and will then be able to dispose of it. Even though HPV is a foreign antigen, it is often not caught immediately by the immune system due to its ability to evade the immune response (Role of Innate). Often, proteins will be displayed on the surface of a virus, but in the case of HPV, there are low levels of viral proteins that are displayed for the immune system, so detection is difficult (HPV-Immune Response). As many vaccines do, an HPV vaccine uses components that are derived from the protein capsid of the virus in question. When injected into the body, the innate immune system is able to “train” the adaptive immune system to recognize the foreign particles as foreign antigen and dispose of it. When the strains of HPV are recognized by the immune system later on, the adaptive portion will recognize it as foreign antigen and destroy it. With many risk factors for HPV and cervical cancer, there have been many attempts to find a vaccine that is effective against all types of HPV, but this has yet to be completed. Before 2015, vaccines prevented around 70% of cervical cancer cases, and in 2015, a new vaccine was approved that can prevent up to 92% of cervical cancer cases (Gardasil-9). Not all variations of HPV can be included in the vaccine, resulting in less than 100% effectiveness; however, the most common variations are included in order for the vaccine to be most effective.

Summary and Conclusions
Human papillomavirus is the primary vehicle for the formation of cervical cancer, especially when combined with other high risk factors such as multiple sexual partners and high sexual activity. Certain proteins such as the E6 and E7 HPV proteins are able to invade developing cells before they proliferate and deregulate the cell cycle, allowing for unregulated growth, leading to cancer in the cervix. As seen in figure 6, this process doesn’t happen all at once, but begins at the stratified squamous epithelium and progresses until it forms a carcinoma and later becomes an invasive cancer cell (EPITHELIAL MESENCHYMAL). Through a process known as EMT, cancerous epithelial cells are able to transition to a mesenchymal cell and are then free to metastasize in other tissues such as the female reproductive tract as well as the bladder, liver, and lungs.
Since HPV is a large source for the formation of cervical cancer, certain vaccinations have been produced to help guard against the virus. When successful, the vaccine is able to protect against the high-risk strains of HPV, stopping the effects of certain HPV proteins on the cell cycle. The primary mechanism for HPV to infect cells and make them cancerous is through the degradation and binding of certain tumor suppressing proteins; however, if the HPV proteins can never interact with the cellular proteins, the cell cycle will continue to be regulated and cancerous cells will not arise from that mechanism.
In conclusion, HPV, a simple virus, plays a large role in the formation of cervical cancer. In its high-risk variations, HPV can introduce proteins that destroy the regulatory process of the cell cycle, introducing the ability for cancerous cells to form and proliferate into normal tissue. While disruption of the cell cycle is usually how cancer begins, the process for cervical cancer is interesting due to its initiation from a virus. The vaccines that protect against the virus aren’t completely effective, but dramatically reduce the chances of becoming infected from HPV and developing cancer later on from that infection.