Daming Chu
Tengteng Liu1- 1Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- 2Department of Oncology, The People’s Hospital of Liaoning Province, Shenyang, China
Background: Uterine Cervical Carcinoma (UCC) is the most prevalent gynecological malignancy globally, with a rising incidence in recent years. Accumulating evidence indicates that specific viral infections, including human papillomavirus (HPV), Epstein-Barr virus (EBV), Hepatitis B and C viruses (HBV and HCV), and human herpesvirus (HHV), may contribute to UCC development and progression. Understanding the complex interplay between viral infections and UCC risk is crucial for developing novel preventative and therapeutic interventions.
Methods: This comprehensive review investigates the association between viral infections and UCC risk by examining the roles of various viral pathogens in UCC etiology and pathogenesis, and possible molecular mechanisms. Additionally, we evaluate current diagnostic methods and potential therapeutic strategies targeting viral infections for UCC prevention or treatment.
Results: The prevention of UCC has been significantly advanced by the emergence of self-sampling for HPV testing as a crucial tool, allowing for early detection and intervention. However, an essential challenge in UCC prevention lies in understanding how HPV and other viral coinfections, including EBV, HBV, HCV, HHV, HIV, or their concurrent presence, may potentially contribute to UCC development. The molecular mechanisms implicated in the association between viral infections and cervical cancer development include: (1) interference of viral oncogenes with cellular regulatory proteins, resulting in uncontrolled cell proliferation and malignant transformation; (2) inactivation of tumor suppressor genes by viral proteins; (3) evasion of host immune responses by viruses; (4) induction of a persistent inflammatory response, contributing to a tumor-promoting microenvironment; (5) epigenetic modifications that lead to aberrant gene expression; (6) stimulation of angiogenesis by viruses; and (7) activation of telomerase by viral proteins, leading to cellular immortalization. Additionally, viral coinfections can also enhance oncogenic potential through synergistic interactions between viral oncoproteins, employ immune evasion strategies, contribute to chronic inflammation, modulate host cellular signaling pathways, and induce epigenetic alterations, ultimately leading to cervical carcinogenesis.
Conclusion: Recognizing the implications of viral oncogenes in UCC etiology and pathogenesis is vital for addressing the escalating burden of UCC. Developing innovative preventative and therapeutic interventions requires a thorough understanding of the intricate relationship between viral infections and UCC risk.
Introduction
Uterine cervical carcinoma (UCC) remains a major global health concern, accounting for significant morbidity and mortality in women worldwide. Despite considerable research efforts and advances in screening and prevention strategies, UCC continues to pose a substantial public health challenge, particularly in low- and middle-income countries (Srinath et al., 2022; Ton et al., 2022; Dau et al., 2023; Tin et al., 2023). A comprehensive understanding of the etiological factors underlying the development of UCC is crucial for devising improved prevention, early detection, and treatment strategies. Although extensive research has been conducted on the etiology and pathogenesis of UCC, the precise mechanisms underlying its development are not yet fully understood. Various factors, such as age (Basoya and Anjankar, 2022; Yuan et al., 2023), obesity (Frumovitz et al., 2014; Coffey et al., 2016; Sassenou et al., 2021; Bohn et al., 2022), hormonal imbalances (Zidi et al., 2020; Iversen et al., 2021; Lasche et al., 2022), genetic predisposition (Chandra et al., 2022; Liu et al., 2022b; Yadav et al., 2023a), and environmental exposures (Kycler et al., 2017; Korsakov et al., 2022), have been implicated in UCC development. Recently, a growing body of evidence has highlighted viral infections, particularly the Human Papillomavirus (HPV), as a key factor in UCC pathogenesis (Figueiredo et al., 2023; Gilham et al., 2023; Smith et al., 2023).
Viruses, as obligate intracellular parasites, are well-recognized for their ability to manipulate host cellular processes, potentially leading to malignant transformation. Several viruses, such as HPV, Epstein-Barr virus (EBV) (Abudoukadeer et al., 2015; Luo et al., 2019), and hepatitis B and C viruses (HBV and HCV) (Mahmood et al., 2002; Ferber et al., 2003), have been identified as oncogenic, playing crucial roles in the pathogenesis of various human cancers. Nevertheless, the association between viral infections and UCC remains an active area of investigation, with inconsistent findings reported in the literature.
This review aims to provide a comprehensive overview of the current state of knowledge regarding the relationship between viral infections and UCC risk. We will discuss the evidence supporting the involvement of various viruses in the development of UCC, focusing on their potential roles in oncogenesis, molecular mechanisms, and clinical implications. Furthermore, we will explore the challenges and future directions in the study of viral infections and UCC, emphasizing the need for well-designed epidemiological and molecular studies to better understand the intricate interplay between viruses and UCC malignancy. Ultimately, elucidating the role of viral infections in UCC may lead to novel preventive and therapeutic strategies for this prevalent and life-threatening disease.
Human papillomavirus (HPV) infection and etiology of UCC
There are over 100 different types of HPV, which are categorized into three risk groups: high-risk, intermediate-risk, and low-risk, based on their association with UCC (Table 1; Muñoz et al., 2003). High-risk HPV types are strongly associated with UCC, as they can cause persistent infections and lead to the development of precancerous lesions, which may eventually progress to cancer. The high-risk types include HPV strains 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 (Table 1). Notably, HPV 16 and 18 are the most common high-risk strains, responsible for approximately 70% of UCC cases worldwide. Two of these species, α9 (also known as HPV16-like) and α7 (also known as HPV18-like), are of particular importance in the context of UCC diagnosis (Table 1; Evans et al., 2022). HPV-16 is a high-risk HPV type belonging to the Alphapapillomavirus genus. It is responsible for nearly 50–60% of all cervical cancer cases, making it the most prevalent and oncogenic HPV type (Youn et al., 2020). The carcinogenic potential of HPV-16 is primarily attributed to the expression of two viral oncoproteins, E6 and E7. These oncoproteins play a crucial role in HPV-16-mediated cervical carcinogenesis by disrupting the normal cellular regulatory pathways. The E6 oncoprotein of HPV-16 targets the tumor suppressor protein p53, promoting its ubiquitin-mediated degradation and thus impairing its ability to regulate cell cycle progression, apoptosis, and DNA repair (Zhang et al., 2022). The E7 oncoprotein, on the other hand, binds to and inactivates the retinoblastoma protein (pRb), a key cell cycle regulator, leading to uncontrolled cell proliferation and genomic instability. Furthermore, E6 and E7 can cooperate to induce chromosomal aberrations, telomerase activation, and immortalization of infected cervical epithelial cells, eventually resulting in malignant transformation (Figure 1; Liu et al., 2019). The strong association between HPV-16 and UCC underscores the importance of HPV vaccination and screening programs to prevent infection and early detection of cervical precancerous lesions. Currently, available prophylactic HPV vaccines, such as the bivalent, quadrivalent, and nonavalent vaccines, provide protection against HPV-16 and other high-risk HPV types. These vaccination programs have been shown to significantly reduce the incidence of HPV-16-associated cervical intraepithelial neoplasia and invasive UCC (Pham et al., 2020). Moreover, persistent HPV-16 infection serves as a valuable biomarker for the early identification of women at high risk for cervical cancer development. Molecular testing for HPV-16 and other high-risk HPV types in cervical cancer screening programs can enhance the sensitivity and specificity of detecting cervical precancerous lesions, thereby improving the overall effectiveness of cervical cancer prevention strategies (Kim et al., 2020).
Table 1. Human papillomavirus (HPV) and uterine cancer risk.
Figure 1. Viral pathogenesis of cervical cancer. The figure highlights the role of viral oncogenes in deregulating cellular processes, leading to uncontrolled cell proliferation and malignant transformation. Additionally, the figure emphasizes the involvement of viral infections in promoting immune escape, chronic inflammation, angiogenesis, and epigenetic modifications. Furthermore, the illustration demonstrates the influence of viruses on the activation of telomerase and the induction of genome instability, contributing to the development of cervical cancer.
Human papillomavirus α9 species includes HPV types 16, 31, 33, 35, 52, and 58. HPV α7 species includes HPV types 18, 39, 45, 59, and 68. These species comprise several high-risk HPV types, which are strongly associated with the development of UCC. UCC diagnosis typically involves a combination of screening and testing methods. Regular UCC screening, such as the Papanicolaou (Pap) test or liquid-based cytology, can identify abnormal cell changes in the cervix. If abnormal cells are detected, additional testing, such as HPV DNA testing or colposcopy, may be recommended. HPV DNA testing helps to identify high-risk HPV types, including those within the α9 and α7 species, that are associated with an increased risk of UCC. HPV α9 and α7 species, which encompass several high-risk HPV types, play a crucial role in the development of UCC. Regular screening, early detection, and appropriate follow-up care are vital for preventing the progression of precancerous lesions into invasive UCC. Additionally, HPV vaccination can help protect against the most common high-risk HPV types, including those in the α9 and α7 species, thereby reducing the risk of UCC. Intermediate-risk HPV types have a weaker association with UCC compared to high-risk types. They include HPV strains 68, 73, and 82 (Table 1). These types may contribute to the development of cancer in combination with other risk factors, but they are not as aggressive as high-risk types. Low-risk HPV types are not typically associated with UCC but can cause benign lesions, such as genital warts or mild dysplasia. These include HPV strains 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108 (Table 1). Although low-risk types do not generally lead to cancer, it is still essential to monitor and treat any HPV infection to maintain overall health. The relationship between UCC and HPV types is based on the risk categories. High-risk types are the primary cause of UCC, while intermediate-risk types have a weaker association, and low-risk types are generally not linked to the development of UCC. Over time, the accumulation of genetic mutations and chromosomal abnormalities in infected cells contributes to the progression from low-grade to high-grade precancerous lesions (cervical intraepithelial neoplasia, CIN) and, eventually, to invasive UCC.
There are several proposed mechanisms by which HPV might contribute to the development of UCC, such as by promoting genomic instability (Porter and Marra, 2022), deregulating cell cycle control (Singh et al., 2022), and inhibiting apoptosis (Figure 1; Yadav et al., 2023b). HPV may downregulate the expression of major histocompatibility complex (MHC) molecules, hindering antigen presentation and recognition by cytotoxic T cells (Ferrall et al., 2021). Viral infections can induce a persistent inflammatory response, characterized by the infiltration of immune cells and the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species. This chronic inflammation may contribute to the formation of a tumor-promoting microenvironment (Hemmat and Bannazadeh Baghi, 2019); HPV infection may cause epigenetic modifications, such as DNA methylation (van den Helder et al., 2022), histone modifications (Lourenço de Freitas et al., 2021), and non-coding RNA regulation (Liu et al., 2022a), which can lead to the aberrant expression of genes involved in cell cycle regulation, apoptosis, and DNA repair, thereby facilitating carcinogenesis (Figure 1). HPV can disrupt the apoptotic machinery, thereby promoting the survival and proliferation of UCC (Liu et al., 2020). HPV can cause genome instability by integrating its viral DNA into the host genome. This integration disrupts the normal function of cellular genes and regulatory elements, leading to the dysregulation of cell cycle control and DNA repair mechanisms (Figure 1; Kamal et al., 2021).
Understanding the molecular biology of HPV infection and UCC development has been crucial in developing prevention and screening strategies, such as HPV vaccines and HPV-based UCC screening tests, to reduce the incidence and mortality of UCC worldwide (Table 1). HPV vaccines, such as Gardasil (Choi et al., 2023) and Cervarix (Roy et al., 2023), protect against the most common high-risk HPV types (particularly HPV 16 and 18). By preventing infection with these types, the vaccines can effectively reduce the likelihood of developing precancerous cervical lesions and, ultimately, UCC. Widespread vaccination has the potential to substantially decrease the overall incidence of UCC. Studies have already shown a decline in the prevalence of high-risk HPV infections and precancerous cervical lesions in vaccinated populations. When a significant portion of a population is vaccinated against HPV, it can create herd immunity, which means that even unvaccinated individuals will be indirectly protected due to reduced virus circulation in the population. Herd immunity, also known as community immunity, occurs when a substantial proportion of a population is immunized against a contagious disease, subsequently reducing the overall circulation of the pathogen and indirectly protecting unvaccinated individuals (Fine et al., 2011). The impact of herd immunity in UCC prevention is particularly relevant given the etiological role of HPV in the development of this malignancy. Persistent high-risk HPV infection is responsible for virtually all cases of UCC (Bosch et al., 2002). Therefore, achieving herd immunity through widespread HPV vaccination has the potential to considerably decrease the incidence of UCC. Several factors contribute to the development of herd immunity in the context of HPV vaccination. Firstly, the widespread vaccination of adolescents, both male and female, can significantly reduce the prevalence of high-risk HPV strains in the population. This reduced prevalence can lead to a decline in the transmission of HPV to unvaccinated individuals, thereby lowering their risk of developing UCC (Markowitz et al., 2012). Secondly, herd immunity can benefit specific population groups that may be at higher risk for HPV infection or cervical cancer but have lower vaccination rates. For example, certain minority or socioeconomically disadvantaged populations might face barriers to accessing HPV vaccination. Herd immunity can provide a measure of protection to these groups by reducing the overall circulation of high-risk HPV strains (Harper and DeMars, 2017). Recent studies have provided evidence of the positive impact of herd immunity on cervical cancer prevention. A study by Drolet et al. found that in countries with high HPV vaccination coverage, the prevalence of vaccine-targeted HPV types decreased by 83% among 13–19-year-old females and 66% among 20–24-year-old females, indicating a substantial reduction in the circulation of high-risk HPV strains (Drolet et al., 2019). Furthermore, the study observed a decrease in HPV prevalence among unvaccinated females, suggesting the presence of herd immunity.
However, it is important to note that HPV vaccines do not protect against all HPV types that can cause UCC, nor do they eliminate the risk entirely. Therefore, even vaccinated individuals should continue to undergo regular UCC screenings as recommended by healthcare professionals. With a reduction in the prevalence of high-risk HPV infections and UCC, there may be a reduced need for frequent UCC screenings (e.g., Pap smears or HPV tests) and associated treatments. This can lead to lower healthcare costs and improved quality of life for women. Self-sampling for HPV testing has emerged as a valuable tool in UCC prevention, offering several benefits that can help improve the overall effectiveness of screening programs and facilitate early detection of HPV infections, particularly among high-risk groups (Racey et al., 2013; Arbyn et al., 2018). Some key advantages of self-sampling for HPV testing during UCC prevention include: Self-sampling allows women to collect their samples in the privacy of their homes, without the need for a clinical appointment. This can lead to higher participation rates, especially among women who may be reluctant or unable to attend traditional clinic-based screenings due to cultural, logistical, or financial barriers (Sancho-Garnier et al., 2013; Gupta et al., 2018). Self-sampling provides a more comfortable and less invasive alternative to clinician-collected samples. Many women find self-sampling less intimidating and more acceptable, which can encourage them to undergo regular HPV testing as part of their UCC prevention routine (Waller et al., 2009; Arrossi et al., 2016). Self-sampling can help reduce costs associated with clinic visits, clinician time, and resources (Abuelo et al., 2014). By facilitating increased participation in HPV testing, self-sampling can contribute to more cost-effective UCC screening programs (Elfström et al., 2014). Self-sampling can improve access to UCC screening among hard-to-reach populations, such as women living in remote areas or those with limited access to healthcare services (Safaeian et al., 2007). By making HPV testing more accessible, self-sampling can help reduce health disparities and improve UCC prevention efforts in underserved communities (Bennett et al., 2018). With increased participation in HPV testing through self-sampling, more women can be screened for high-risk HPV infections. Early detection of these infections allows for timely intervention, such as close monitoring or treatment, to prevent the development of precancerous lesions and UCC (Ronco et al., 2014). It is important to note that the accuracy of self-sampling depends on the quality of the sample collected and the type of HPV test used (Arbyn et al., 2014). High-quality self-sampling kits and sensitive HPV tests are essential for reliable results (Petignat et al., 2007). In conclusion, self-sampling for HPV testing is an important tool in UCC prevention, as it can increase participation rates, improve access to screening, and facilitate early detection and intervention, ultimately contributing to a reduction in the incidence of UCC (Ogilvie et al., 2007; Nelson et al., 2017). It is important to consider other risk factors for UCC, such as obesity (Urbute et al., 2022), smoking (Table 1; Hildesheim et al., 2001; Malevolti et al., 2022), hormone replacement therapy, tamoxifen use, and a family history of Lynch syndrome (Kwolek et al., 2023), as these factors have more consistent associations with UCC risk.
The role of EBV in UCC risk
Epstein-Barr virus, also known as human herpesvirus 4 (HHV-4), is a virus that has been associated with various types of cancers, including Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, and some types of stomach cancer (gastric carcinoma). However, the association between EBV and UCC is not well-established. Some studies have detected EBV DNA or viral proteins in UCC tissues (Blanco et al., 2020; Castro et al., 2020; Feng M. et al., 2021; Macleod and Reynolds, 2021), while others have not found any significant association between EBV infection and UCC (Table 2; De Oliveira et al., 1999; Noel et al., 2001).
Table 2. Association of Epstein-Barr virus (EBV) with UCC risk.
Several mechanisms have been proposed to elucidate the role of EBV in the development of UCC. Two crucial viral proteins, Epstein-Barr nuclear antigen 1 (EBNA-1) and latent membrane protein 1 (LMP-1), have been implicated in the oncogenic process during EBV infection. EBNA-1 is a multifunctional protein involved in the replication, maintenance, and segregation of the EBV episome in latently infected cells. It is expressed in all EBV-associated malignancies and plays a pivotal role in the persistence of viral episomes within host cells. Additionally, EBNA-1 contributes to the immortalization of infected cells by altering cellular gene expression and promoting genomic instability. During clinical diagnosis, the detection of EBNA-1 expression may serve as a marker of latent EBV infection and its associated cervical malignancies (Hoseini Tabatabaie et al., 2023). LMP-1, on the other hand, is a transmembrane protein that functions as a constitutively active mimic of the tumor necrosis factor receptor (TNFR) family, stimulating multiple signaling pathways that promote cell survival, proliferation, and differentiation. LMP-1 exerts its oncogenic effects by activating the nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. Detection of LMP-1 expression during clinical diagnosis can indicate the presence of an active EBV infection and suggest a more aggressive disease course, as LMP-1 is implicated in immune evasion, angiogenesis, and metastasis (Awasthi et al., 2023). A well-executed retrospective cohort study contributes to our understanding of the prevalence of EBV by targeting EBNA-1 and LMP-1 in cervical cancer specimens, with the authors reporting a 22.2% prevalence (n = 22) in their cohort of 99 patients. This is a valuable addition to the existing body of knowledge on EBV and cervical cancer. The authors provide evidence for the prognostic value of EBV status in cervical cancer patients, demonstrating that the 1-year and 5-year OS rates were higher in the EBV-positive group compared to the EBV-negative group. This finding highlights the potential clinical utility of EBV status as a prognostic biomarker (Table 2; Castro et al., 2020). EBV infection has been associated with epigenetic modifications in host cells, including DNA methylation (Fujii et al., 2022), histone modifications (Fujii et al., 2022), and non-coding RNA regulation (Kolesnik et al., 2021). EBV has developed various strategies to evade the host immune response, allowing the virus to persist in infected cells. This immune evasion can lead to chronic inflammation and contribute to the development of a favorable microenvironment for UCC initiation and progression (Figure 1; Pandey et al., 2021).
There have been some studies suggesting that coinfection with EBV and HPV may increase the risk of UCC development. The hypothesis is that the two viruses could act synergistically, with EBV potentially promoting HPV-induced cervical carcinogenesis (Table 2; da Carvalho and de Melo, 2019; Blanco et al., 2020). Co-infection with EBV, HPV, and human immunodeficiency virus (HIV) could potentially increase the risk of UCC development (Denny et al., 2008; Kelly et al., 2018). Infection with these high-risk types can lead to the formation of abnormal cervical cells, which may progress to UCC if not detected and treated early. HIV infection impairs the immune system, making it more difficult for the body to fight off infections, including HPV. Women with HIV are more likely to have persistent HPV infections, which can increase the risk of developing UCC (Clifford et al., 2017). Additionally, HIV-infected women are more likely to have faster progression from pre-cancerous lesions to invasive UCC compared to women without HIV. Although EBV is not directly linked to UCC, co-infection with HIV could further increase the risk due to the impaired immune response. Co-infections can complicate the clinical picture, and it is essential for healthcare providers (Table 2; Feng M. et al., 2021). HPV, EBV, and KSHV coinfections can stimulate angiogenesis (Figure 1), the formation of new blood vessels, by upregulating pro-angiogenic factors (e.g., VEGF and IL-8), which may promote tumor growth and metastasis (Dai et al., 2018; Hemmat and Bannazadeh Baghi, 2019). Upon coinfection, EBV and HPV oncoproteins have been shown to cooperatively activate several critical signaling pathways, including PI3K/AKT, MAPK/ERK, JAK/STAT, β-catenin, and p53 (Vranic et al., 2018). These pathways are known to regulate various cellular processes, such as cell survival, proliferation, differentiation, and migration, which are often dysregulated in cancer. Consequently, the simultaneous activation of these pathways by EBV and HPV oncoproteins can contribute to enhanced UCC development and progression.
Given the current state of research, the direct relationship between EBV and UCC risk remains unclear. Further studies are needed to investigate the potential association between EBV and uterine cancer, as well as the underlying mechanisms involved if such a link exists.
HBV and HCV infection increases the development of UCC risk indirectly
Hepatitis B viruses is a DNA virus that primarily infects the liver and can cause both acute and chronic hepatitis. HBV is a well-established risk factor for liver cancer, specifically hepatocellular carcinoma (HCC). However, the association between HBV infection and uterine cancer, particularly UCC, is not well-established. There is limited research on the potential relationship between HBV and uterine cancer, and the available studies do not provide sufficient evidence to establish a clear link between HBV infection and the risk of developing uterine cancer (Table 3). It is important to note that HBsAg (hepatitis B surface antigen) is associated with hepatitis B infection, which primarily affects the liver, while HPV is the main causative agent for UCC. Both HBV and HPV infection can potentially contribute to a weakened immune system, which may make it more difficult for the body to fight off other infections, including HPV. A weakened immune system could theoretically increase the risk of developing UCC in HPV positive individuals, but the primary risk factor remains the HPV infection itself (Table 3; Ferber et al., 2003; Luo et al., 2022). Although there is not a direct causal link between HBV infection and squamous cell UCC, some studies have suggested a potential association between the two. Serological markers of HBV infection, such as HBsAg, hepatitis B e antigen (HBeAg), and hepatitis B core antibody (anti-HBc), can provide information about the presence and stage of HBV infection in an individual. These markers may have prognostic value in certain cancer types (Table 3; Feng X. et al., 2021). The presence of HBsAg in serum indicates an ongoing infection, either acute or chronic (Lok and McMahon, 2009). HBeAg is a secreted viral protein that reflects active viral replication and is associated with high infectivity (Hadziyannis, 1995). Anti-HBc is an antibody produced in response to the HBcAg, which is a component of the viral nucleocapsid. The presence of anti-HBc indicates previous exposure to HBV, either resolved or ongoing (Chu and Liaw, 2010). In a study involving 277 cervical cancer patients, the seropositivity rates for HBsAg, HBeAg, and anti-HBc were found to be 4.33, 0.72, and 13.00%, respectively, indicating a potential relationship between HBV infection and cervical cancer (Wu et al., 2021). The detection of HBsAg and HBcAg in a subset of cervical cancer cases with seropositive HBsAg, as well as the increased risk of cervical cancer in individuals with both HBsAg and HPV positive, underscores the potential interplay between HBV infection and HPV in cervical cancer development. This observation highlights the importance of considering co-infections when examining UCC risk factors (Luo et al., 2022).
Table 3. The indirect association between hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and the increased risk of developing uterine cervical Cancer (UCC).
Hepatitis C viruses is a well-known risk factor for liver cancer, particularly hepatocellular carcinoma. However, its association with uterine cancer, particularly UCC, is unclear and not well-established (Table 3; Mahmood et al., 2002; Chhetri, 2010). The prevalence of HBV and HCV infections was found among UCC patients compared to the general population. The association between chronic HBV infection and cervical cancer disappears among HPV-positive patients but remains significant for patients younger than 50 years after adjusting for HPV infection and parity. Co-infection with sexually transmitted infections (STIs), such as HIV, HBV, HCV, can also increase the risk of developing UCC. The seroprevalence of STIs among cervical cancer suspected women in Ethiopia, highlights a significant public health concern. The authors report an overall STI prevalence of 16.6% (67/403) in the study population, with the prevalence of HIV, HBV, HCV, and syphilis being 8.9, 2.5, 1, and 7.2%, respectively. This information helps to bridge the existing knowledge gap concerning the burden of coinfection in this UCC population (Abebe et al., 2021).
The clinical importance of EBV, HBV, and HCV in the etiology of cervical cancer has become an area of increasing interest among researchers and clinicians. The exact mechanisms by which EBV may contribute to cervical cancer development remain unclear, but possible explanations include the induction of genomic instability, inhibition of apoptosis, and promotion of cell proliferation (Figure 1). The possible mechanisms through which HBV may contribute to chronic inflammation, immune suppression, or molecular mimicry. Further investigation is warranted to determine the clinical relevance of HBV in the context of cervical cancer and to assess whether prevention and control of HBV infection may have implications for cervical cancer risk reduction. Similar to HBV, HCV is primarily implicated in liver diseases but has also been suggested as a possible co-factor in cervical cancer development. Some studies have reported an increased prevalence of HCV infection among cervical cancer patients, raising the possibility of an association between the two conditions. The potential mechanisms linking HCV to cervical cancer remain speculative and may involve chronic inflammation or immune dysregulation. In conclusion, the clinical importance of EBV, HBV, and HCV in cervical cancer etiology remains an emerging area of investigation. Although these viruses are not considered primary causative agents of cervical cancer, their potential role in the development of this malignancy warrants further study. Understanding the mechanisms through which these viruses may contribute to cervical carcinogenesis could have important implications for the prevention, diagnosis, and treatment of cervical cancer, ultimately improving patient outcomes and public health strategies.
Other virus strains and UCC risk
Human cytomegalovirus (HCMV) has been associated with various malignancies, including glioblastoma and prostate cancer. It has been detected in some UCC tissues (Kienka et al., 2019; Khashman et al., 2020b; Ghadicolaee et al., 2021), but the relationship is not well-established. Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus known to be associated with adult T-cell leukemia/lymphoma (ATL) and a neurological disorder called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although HTLV-1 has not been directly implicated in UCC, some studies have suggested a potential link between HTLV-1 infection and an increased risk of developing UCC (Schierhout et al., 2020). The connection between HTLV-1 and UCC is not as well-established as that of HPV, which is the primary cause of UCC. However, there is some evidence to suggest that HTLV-1 infection might influence the persistence or progression of HPV infection, potentially increasing the risk of UCC in HTLV-1-infected women (Ibrahim Jaber and Qasim Dhumad, 2022; Rosadas and Taylor, 2022). Additionally, it has been suggested that HTLV-1 might indirectly contribute to UCC development by impairing the immune system and reducing the body’s ability to control HPV infection (Ibrahim Jaber and Qasim Dhumad, 2022).
Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is a virus primarily associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. While KSHV has been extensively studied in relation to these conditions, its direct association with UCC is not well-established. Although KSHV and HPV are both viruses that can cause cancer, their roles in the development of UCC are distinct. HPV is considered the primary etiological agent for UCC, while KSHV has not been definitively linked to this malignancy. There have been some studies investigating the potential role of KSHV in UCC (Mukerebe, 2022), but the evidence is not yet strong enough to establish a direct association. Further research is needed to determine if KSHV plays a role in the development or progression of UCC or if it has any interaction with HPV in cervical carcinogenesis.
Human herpesvirus (HHV), particularly HHV-2, also known as herpes simplex virus type 2 (HSV-2), has been suggested to play a role in the development of UCC (Mukerebe, 2022). HSV-2 is primarily responsible for genital herpes infections, which can cause genital ulcers and increase the risk of acquiring other sexually transmitted infections (STIs), including HPV (Moharreri and Sohrabi, 2021). While HSV-2 itself is not considered a direct cause of UCC, its association with genital ulcers and the increased risk of acquiring HPV could potentially contribute to the development of UCC. Furthermore, HSV-2 infection might cause local inflammation and immunosuppression in the cervical area, which could facilitate the persistence and progression of HPV infection, ultimately leading to UCC (Vitali et al., 2020).
Human immunodeficiency virus is a virus that attacks the immune system, specifically the CD4 + T cells, which play a crucial role in immune response. HIV infection can progress to acquired immunodeficiency syndrome (AIDS) when the immune system is severely damaged, leaving the individual vulnerable to various opportunistic infections and cancers. There is a strong association between HIV and UCC. HIV infection weakens the immune system, making it difficult for the body to fight off HPV infections and prevent the progression of pre-cancerous lesions to UCC (Marima et al., 2021; Stelzle et al., 2021). HIV-infected women have a higher prevalence of HPV infection and are more likely to be infected with multiple high-risk HPV types. They are also more likely to have persistent HPV infections, which increases the risk of developing UCC (D’andrea et al., 2019). HIV-infected women tend to have a faster progression from HPV infection to the development of precancerous lesions and invasive UCC compared to women without HIV infection (Moscicki et al., 2019; Tawe et al., 2020). HIV-infected women may have a poorer response to UCC treatments, such as surgery, radiation, and chemotherapy, due to their compromised immune systems. To reduce the risk of UCC in HIV-infected women, regular UCC screening (e.g., Pap smears or HPV tests) is recommended. Additionally, the administration of the HPV vaccine can help protect against the high-risk HPV types responsible for UCC. Antiretroviral therapy (ART) can also help to improve the immune system in HIV-infected individuals, potentially reducing the risk of developing UCC (Shin et al., 2019). It is important to note that the link between many types of viruses and UCC is still not fully understood, and more research is needed to establish a clear relationship between the two. HPV remains the primary risk factor for UCC, and the prevention and control of HPV infection through vaccination and screening are the most effective strategies for reducing the incidence of UCC. More research is needed to determine the exact relationship between different virus types and UCC, as the current evidence is limited and inconclusive.
The future challenge for the viral etiology of UCC
The future challenges for the viral etiology of UCC, particularly in relation to HPV, include (1) Improving vaccination coverage, although the HPV vaccine has proven effective in reducing the prevalence of high-risk HPV strains associated with UCC, improving vaccination coverage globally remains a challenge, especially in low- and middle-income countries where the burden of UCC is high; (2) Understanding HPV and other viral coinfections, such as EBV, may potentially play a role in UCC development. Further research is needed to elucidate the mechanisms and significance of these coinfections; (3) expanding screening programs: screening programs using HPV DNA testing have shown promise in detecting precancerous lesions, but implementing and expanding these programs worldwide, particularly in resource-limited settings, remains a challenge; (4) addressing disparities in access to care, disparities in access to preventive care, such as vaccination and screening, contribute to the high burden of UCC in certain populations. Efforts should be made to address socioeconomic, cultural, and logistical barriers to care; (5) developing novel therapeutic approaches, although current treatments for UCC, such as surgery, radiation, and chemotherapy, can be effective, there is a need for novel therapies that target the viral etiology of the disease, such as antiviral drugs and immunotherapies; (6) enhancing public awareness and education, public awareness and understanding of the role of HPV in UCC and the importance of vaccination and screening are essential to reduce the burden of the disease. Educational campaigns targeting various populations can help increase vaccine uptake and participation in screening programs; (7) investigating the role of viral genetic variation, the role of genetic variation within HPV types and its impact on UCC risk and vaccine efficacy needs further investigation; (8) Studying the impact of the HPV vaccine on non-cervical HPV-associated cancers, the HPV vaccine has the potential to prevent other HPV-associated cancers, such as oropharyngeal, anal, and penile cancers. Further research is needed to understand the long-term impact of vaccination on these cancers; (9) Addressing vaccine hesitancy: Vaccine hesitancy remains a challenge in certain populations, and efforts should be made to address misconceptions and promote confidence in the HPV vaccine, and (10) Long-term monitoring and surveillance, continued monitoring and surveillance of HPV prevalence, vaccine efficacy, and UCC incidence are crucial to assess the long-term impact of vaccination and screening programs and inform public health policy.
Author contributions
DC and TL: review conception, design, data collection, and quality analysis. TL and YY: the data extraction of the included studies, analysis, and interpretation of results. DC and YY: draft manuscript preparation and the critical revision of the manuscript. All authors reviewed the results and approved the final manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Keywords: human papillomavirus (HPV), Epstein-Barr virus (EBV), human herpesvirus (HHV), uterine cervical carcinoma (UCC), molecular mechanisms, hepatitis B and C viruses (HBV and HCV)
Citation: Chu D, Liu T and Yao Y (2023) Implications of viral infections and oncogenesis in uterine cervical carcinoma etiology and pathogenesis. Front. Microbiol. 14:1194431. doi: 10.3389/fmicb.2023.1194431
Received: 27 March 2023; Accepted: 05 May 2023;
Published: 24 May 2023.
Edited by:
Jinlin Li, Uppsala University, SwedenReviewed by:
Hussein O. M. Al-Dahmoshi, University of Babylon, IraqValentina Dell’Oste, University of Turin, Italy
Copyright © 2023 Chu, Liu and Yao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Daming Chu, gglkdd@163.com