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INTERNATIONAL CONGRESS OF

CancerGenetics

• The Interplay of HPV Oncoproteins, Tumor Microenvironment, and Extracellular Vesicles in Cervical Cancer Progression

• Narges Mousavi,¹ Yasaman Baharvand ,^2,*
  1. Midwifery Department, Faculty of nursing and midwifery, Ahvaz Jondishapur University of Medical Sciences
  2. Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
  
  
  
• Introduction: Cervical cancer (CC) is a major global health concern, ranking as the fourth most common cancer in women worldwide and the second leading cause of cancer-related deaths in women aged 20–39 years (1,2)Human papillomavirus (HPV), a small, nonenveloped, double-stranded DNA virus from the Papillomaviridae family, is the primary etiological factor, with over 400 types identified, all exhibiting tropism for cutaneous or mucosal epithelia (3,4). HPV is the most common sexually transmitted infection, causing approximately 5% of all cancers globally, with 3–3.5% attributed to HPV16(1,5). HPV has twelve mucosa-associated HPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) as potent biological carcinogens, contributing to 4.1% of the global cancer burden per 2018 GloboCAN estimates(3). High-risk HPV (HR-HPV) types, particularly HPV16 and HPV18, are strongly linked to cervical, anal, oropharyngeal, penile, vaginal, and vulvar cancers, as well as cervical intraepithelial lesions(2,4,5). HPV infection typically involves acquisition, clearance or persistence, and possible progression to precancer or invasive cancer; about 90% of infections are cleared by the immune system within two years, while 10–15% persist, increasing the risk of malignant transformation (6). Early cervical cancer often lacks symptoms, making it prone to misdiagnosis and highlighting the need for sensitive biomarkers for early detection (2).
• Methods: We searched PubMed and Google Scholar for articles related to cervical. The main keywords used were HPV, E6/E7 oncoproteins, tumor microenvironment, extracellular vesicles, microRNAs, immune evasion, and biomarkers and relevant studies were included.
• Results: Persistent HR-HPV infection, particularly with HPV16 and HPV18, drives cervical carcinogenesis through the E6 and E7 oncoproteins, which disrupt cell cycle regulation, DNA damage response, and apoptosis, leading to genomic instability and cellular transformation(1,2,4,5). The E6 oncoprotein complexes with E6AP ubiquitin ligase and p53, promoting proteasomal degradation and blocking apoptosis, while E7 binds pRB, releasing E2F and causing cell cycle deregulation(2). These oncoproteins also activate signaling pathways (PI3K/AKT, Wnt, Notch) and affect cytokine expression, fostering an immunosuppressive tumor microenvironment (TME) that promotes tumor growth, metastasis, and therapeutic resistance(5,6). The TME, comprising tumor cells, bone marrow-derived cells, and stromal cells, exhibits increased immune infiltration, T cell activation, and immunoregulatory stimuli in HPV-positive cervical cancers compared to HPV-negative counterparts, a pattern also observed in HPV-positive head and neck cancers (3,5). Polarization of tumor-associated macrophages (TAMs) from M1 to M2 phenotypes within the TME enhances immune evasion, carcinogenesis, and metastasis (2). Extracellular vesicles (EVs), spherical membrane-derived particles released by nearly all cells, including tumor cells, play a critical role in both physiological and pathological processes, including cancer metastasis(3,6). EVs from HPV-infected cells contain viral DNA, proteins, and nucleic acids, including E6/E7 oncoproteins and microRNAs (miR-21, miR-146a), which are transferred to target cells, promoting angiogenesis, migration, invasion, and TME remodeling independent of infectious virion production(1,6). Elevated miR-21 and miR-146a levels in cervicovaginal lavage from HPV-positive healthy women and cervical cancer patients suggest their potential as biomarkers (6). HR-HPV oncoproteins also modulate miRNA expression through altered methylation in high-grade cervical intraepithelial neoplasia and CC cells (4). EVs carry inflammatory mediators (cytokines, chemokines, enzymes), further remodeling the TME to support tumor progression(1). Beyond cervical cancer, HR-HPV DNA is detected in epithelial ovarian cancer (EOC) tissues and fallopian tubes, with E6/E7 oncoproteins potentially contributing to ovarian tumorigenesis through immune dysregulation, inflammation, and disruption of cellular pathways, though their role in EOC remains unclear (1,7). The persistence of HR-HPV infection, influenced by the local microenvironment, enhances malignant transformation, but the mechanisms are not fully understood(6). These findings highlight the critical roles of the TME, EVs, and HPV oncoproteins in cervical cancer progression and suggest EV-associated miRNAs as promising biomarkers for early detection and diagnosis.
• Conclusion: Cervical cancer is mainly caused by persistent high-risk HPV and it remains a global health challenge. The viral proteins E6 and E7 disrupt cell control and weaken immune defenses, while EVs carry viral material and microRNAs like miR-21 and miR-146a, which may serve as biomarkers. Despite advances in vaccines and screening, more research is needed on HPV persistence, TME remodeling, and EV-mediated communication to develop targeted therapies.
• Keywords: Cervical cancer, HPV, TME, EVs