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15 pages, 5314 KiB

Open AccessArticle

The Expression of HPV-16 E5 Oncoprotein Impacts the Transcript Profiles of FGFR2 and EMT-Related Genes in Preneoplastic Anal Epithelium Lesions

by Salvatore Raffa, Vanessa Mancini, Deborah French, Francesca Rollo, Maria Benevolo, Eugenia Giuliani, Maria Gabriella Donà, Danilo Ranieri and Francesca Belleudi

Int. J. Mol. Sci. 2024, 25(22), 12085; https://doi.org/10.3390/ijms252212085 - 11 Nov 2024

Viewed by 327

Abstract

Anal Squamous Cell Carcinoma (SCCA) is a rare Human Papillomavirus type 16 (HPV16)-associated carcinoma whose pathogenesis is still poorly understood. Recent studies based on biopsy and Next Generation Sequencing (NGS) approaches have linked the viral episomal status to aggressive SCCA phenotypes, suggesting a [...] Read more.

Anal Squamous Cell Carcinoma (SCCA) is a rare Human Papillomavirus type 16 (HPV16)-associated carcinoma whose pathogenesis is still poorly understood. Recent studies based on biopsy and Next Generation Sequencing (NGS) approaches have linked the viral episomal status to aggressive SCCA phenotypes, suggesting a potential role of the 16E5 oncoprotein in tumor development. Our previous findings indicated that 16E5 induces Fibroblast Growth Factor Receptor 2 (FGFR2) isoform switching, aberrant mesenchymal FGFR2c expression, Epithelial Mesenchymal Transition (EMT), and cell invasion in various in vitro human keratinocyte models, as well as in the in vivo context of cervical Low-grade Squamous Intraepithelial Lesions (LSILs). To further explore the role of 16E5 in epithelial carcinogenesis, this study aims to investigate the molecular profile in HPV-related anal lesions. The results showed a significant positive correlation between 16E5 and FGFR2c, as well as 16E5 or FGFR2c and key EMT-related transcription factors, particularly in the group of HPV16 positive anal samples not containing without high grade lesions. Additionally, by coupling the molecular analysis with an interactome investigation, we hypothesized a potential functional interplay between the Ca²⁺ channel Transient Receptor Potential Ankyrin 1 (TRPA1) and FGFR2c, mediated by 16E5 during the establishment of the oncogenic signaling. These findings will help to elucidate the actual relevance of 16E5 in the early progression of anal lesions and contribute to determine its potential as target for future preventive approaches for HPV16-positive SCCA. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Human Papillomavirus Family (HPV) Induced Oncogenesis)

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11 pages, 251 KiB

Open AccessArticle

Evaluation of the Use of Methylation as a New Tool for the Diagnostics and Progression of Squamous Intraepithelial Lesions

by Dominik Pruski, Sonja Millert-Kalińska, Agata Lis, Ewa Pelc, Przemysław Konopelski, Robert Jach and Marcin Przybylski

Int. J. Mol. Sci. 2024, 25(22), 11863; https://doi.org/10.3390/ijms252211863 - 5 Nov 2024

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Abstract

Vaccination against human papillomavirus (HPV) significantly reduces the incidence of HPV-related lesions worldwide. Considering the increasingly young age of patients in gynecological offices and earlier sexual initiation and potential contact with the HPV virus, doctors need the tools to verify diagnoses. Currently, women [...] Read more.

Vaccination against human papillomavirus (HPV) significantly reduces the incidence of HPV-related lesions worldwide. Considering the increasingly young age of patients in gynecological offices and earlier sexual initiation and potential contact with the HPV virus, doctors need the tools to verify diagnoses. Currently, women plan to pursue motherhood later, so it is necessary to consider whether sexual treatment in the form of, among others, loop electrosurgical excision procedures (LEEPs) may increase the risk of premature birth or difficulty dilating the cervix during labour. For this reason, to avoid the overtreatment of low-grade squamous intraepithelial lesions (LSILs), methylation testing may be considered. In patients with histopathologically confirmed high-grade squamous intraepithelial lesions (HSILs) during biopsy and, ultimately, a lower diagnosis, i.e., LSIL or no signs of atypia, methylation was found to be a useful tool. We performed a Pap smear, HPV genotyping, a punch biopsy, LEEP-conization (if needed), and methylation tests on 108 women admitted to the District Public Hospital in Poland. Women with a negative methylation test result were significantly more likely to be ultimately diagnosed with LSIL (p = 0.013). This means that in 85.7% of the patients with HSIL, major cervical surgery could be avoided if the methylation test was negative. Methylation testing, as well as dual-staining and diagnostics detecting the mRNA transcripts of highly oncogenic types of HPV, might be used in the future in the diagnosis of pre-cancerous conditions, mainly of the cervix, and in HPV-dependent cervical cancer screening. The methylation test may also be used in the diagnosis and identification of lesions within the cervical canal, including those located deep within the frontal crypts, not visible even during a professional colposcopic evaluation of the cervix. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Human Papillomavirus Family (HPV) Induced Oncogenesis)

11 pages, 817 KiB

Open AccessArticle

Ficus carica Latex Modulates Immunity-Linked Gene Expression in Human Papillomavirus Positive Cervical Cancer Cell Lines: Evidence from RNA Seq Transcriptome Analysis

by Muharrem Okan Cakir, Ugur Bilge, Declan Naughton and G. Hossein Ashrafi

Int. J. Mol. Sci. 2023, 24(17), 13646; https://doi.org/10.3390/ijms241713646 - 4 Sep 2023

Cited by 1 | Viewed by 1864

Abstract

Cervical carcinogenesis is the leading cause of cancer-related deaths in women, and the role of high-risk human papillomavirus (HR-HPV) as a possible risk factor in the development of this cancer is well recognized. Despite the availability of multi-therapeutic approaches, there is still major [...] Read more.

Cervical carcinogenesis is the leading cause of cancer-related deaths in women, and the role of high-risk human papillomavirus (HR-HPV) as a possible risk factor in the development of this cancer is well recognized. Despite the availability of multi-therapeutic approaches, there is still major concern regarding the prevention of metastatic dissemination and excessive tissue injuries. Therefore, it is imperative to develop a safer and more efficient treatment modality. Ficus carica, a natural plant, has shown potential therapeutic properties through its fruit latex when applied to HPV-positive cervical cancer cell lines. However, the mechanisms of action of Ficus carica (fig) latex are not well understood. This study aims to provide a deeper insight into the biological activities of fig latex on human cervical cancer cell lines expressing high-risk HPV types 16 and 18. The data obtained from this study reveal that fig latex influences the expression of genes involved in “Class I MHC-mediated antigen presentation” as well as “Antigen processing: Ubiquitination and Proteasome degradation”. These genes play a crucial role in host immune surveillance and the resolution of infection. Notably, Western blot analysis corroborated these findings, demonstrating an increase in the expression of MHC class I in HeLa cells after fig latex treatment. Findings from this study suggest that fig latex may enhance T cell responses against oncogenic HPV, which could be beneficial for the clearance of early-stage cancer. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Human Papillomavirus Family (HPV) Induced Oncogenesis)

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18 pages, 4073 KiB

Open AccessArticle

Sequence-Dependent Interaction of the Human Papillomavirus E2 Protein with the DNA Elements on Its DNA Replication Origin

by Gulden Yilmaz, Esther E. Biswas-Fiss and Subhasis B. Biswas

Int. J. Mol. Sci. 2023, 24(7), 6555; https://doi.org/10.3390/ijms24076555 - 31 Mar 2023

Cited by 5 | Viewed by 2006

Abstract

The human papillomavirus (HPV) E2 protein is essential for regulating the initiation of viral DNA replication as well as the regulation of transcription of certain HPV-encoded genes. Its ability to recognize and bind to its four recognition sequences in the viral origin is [...] Read more.

The human papillomavirus (HPV) E2 protein is essential for regulating the initiation of viral DNA replication as well as the regulation of transcription of certain HPV-encoded genes. Its ability to recognize and bind to its four recognition sequences in the viral origin is a key step in the initiation of HPV DNA replication. Thus, understanding the mechanism of DNA binding by E2 protein and the unique roles played by individual DNA sequence elements of the replication origin is essential. We have purified the recombinant full-length HPV type 11 E2 protein. Quantitative DNA binding analysis indicated E2 protein bound all four DNA binding sites with reasonably high affinities but with distinct preferences. It bound its cognate binding sites 1, 2, and 4 with higher affinities, but bound binding site 3 with lower affinity. Analysis of binding to these sites unraveled multiple sequence elements that appeared to influence E2 binding affinity and target discrimination, including the sequence of spacer region, flanking sequences, and proximity of E2 binding sites. Thermodynamic analysis indicated hydrophobic interaction in the protein-DNA complex formation. Our studies indicate a large multi-protein complex formation on the HPV-origin DNA, likely due to reasonably high binding affinities as well as intrinsic oligomerization propensity of E2 dimers. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Human Papillomavirus Family (HPV) Induced Oncogenesis)

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11 pages, 2504 KiB

Open AccessArticle

Differential Urinary Proteomic Analysis of High-Risk Cervical Intraepithelial Neoplasia

by Peter Bober, Soňa Tkáčiková, Ivan Talian, Peter Urdzík, Silvia Toporcerová and Ján Sabo

Int. J. Mol. Sci. 2023, 24(3), 2531; https://doi.org/10.3390/ijms24032531 - 28 Jan 2023

Cited by 1 | Viewed by 2527

Abstract

Human papillomavirus (HPV)-associated lesions and malignancies exhibit alterations in the composition and functionality of the extracellular matrix (ECM) that represent the complex molecular pathways present between infection and disease. A total of 20 urine samples were used, including from 10 patients with cervical [...] Read more.

Human papillomavirus (HPV)-associated lesions and malignancies exhibit alterations in the composition and functionality of the extracellular matrix (ECM) that represent the complex molecular pathways present between infection and disease. A total of 20 urine samples were used, including from 10 patients with cervical intraepithelial neoplasia grade 3 (CIN3) and 10 healthy controls to perform the label-free quantitative analysis using the nano-HPLC and ESI-MS ion trap mass analyzer and matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI-TOF/MS) fast screening. Among 476 identified/quantified proteins, 48 were significantly changed (log₂-fold change ≥1.0 or ≤−1.0, −log10 (bbinominal, p-value ≥ 1.3), of which were 40 proteins (down-regulated) and 8 proteins (up-regulated) in CIN3, in comparison to healthy controls. The biological function and key pathway enrichment of the gene set using gen set enrichment analysis (GSEA) were analyzed. The ECM-receptor interaction pathway (NES = −1.64, p = 0.026) was down-regulated by 13 proteins (HSPG2, COL6A1, COL6A3, SPP1, THBS1, TNC, DAG1, FN1, COMP, GP6, VTN, SDC1, and CD44; log₂ FC range from −0.03 to −1.48) for the CIN3 group in the KEGG database. The MALDI-TOF/MS screening showed the difference of protein profiles between the control and CIN3 groups, i.e., using the scatter plot with a well-separated shape, as well as effectively distinguishing both groups (control and CIN3) using genetic algorithms (GA) with cross-validation (51.56%) and recognition capability (95.0%). Decreased levels of ECM-receptor interaction proteins may cause disturbances in the interactions of cells with the ECM and play an important role in the development and progression of cervical cancer. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Human Papillomavirus Family (HPV) Induced Oncogenesis)

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Review

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21 pages, 547 KiB

Open AccessReview

The Role of microRNA Expression and DNA Methylation in HPV-Related Cervical Cancer: A Systematic Review

by Alessandra Pulliero, Giulia Cassatella, Pietro Astuni, Zumama Khalid, Stefano Fiordoro and Alberto Izzotti

Int. J. Mol. Sci. 2024, 25(23), 12714; https://doi.org/10.3390/ijms252312714 (registering DOI) - 26 Nov 2024

Abstract

Human papillomavirus (HPV) infection is a major etiologic factor in cervical cancer, a major cause of cancer-related morbidity and mortality among women worldwide. The role of microRNA (miRNA) dysregulation in cervical carcinogenesis is still largely unknown, but epigenetic changes, including DNA methylation and [...] Read more.

Human papillomavirus (HPV) infection is a major etiologic factor in cervical cancer, a major cause of cancer-related morbidity and mortality among women worldwide. The role of microRNA (miRNA) dysregulation in cervical carcinogenesis is still largely unknown, but epigenetic changes, including DNA methylation and miRNA regulation, are crucial factors. The integration of HPV DNA into the host genome can lead to alterations in DNA methylation patterns and miRNA expression, contributing to the progression from normal epithelium to cervical intraepithelial neoplasia and, ultimately, to cervical cancer. This review aimed to examine the relationship between epigenetic changes in the development and progression of HPV associated with cervical cancer. A systematic literature search was conducted in major databases using predefined inclusion and exclusion criteria. Studies that investigated the expression, function, and clinical significance of miRNAs, DNA methylation, and the expression of oncoproteins in HPV-related cervical cancer were included. Data extraction, quality assessment, and synthesis were performed to provide a comprehensive overview of the current state of knowledge. We provide an overview of the studies investigating miRNA expression in relation to cervical cancer progression, highlighting their common outcomes and their weaknesses/strengths. To achieve this, we systematically searched the Pubmed database for all articles published between January 2018 and December 2023. Our systematic review revealed a substantial body of evidence supporting the pivotal role of miRNA dysregulation in the pathogenesis of HPV-related cervical cancer and related oncoproteins. From the 28 studies retrieved, miR-124, FAM194/miR-124-2, and DNA methylation are the most frequently down- or up-regulated in CC progression. Notably, FAM194/miR-124-2 and DNA methylation emerged as a promising molecular marker for distinguishing between cases requiring immediate surgical intervention and those amenable to a more conservative wait-and-see approach. This systematic review underscores the critical involvement of microRNA in the context of HPV-related cervical cancer and sheds light on the potential clinical utility of FAM194/miR-124-2 and DNA methylation as a discriminatory tool for guiding treatment decisions. The identification of patients who may benefit from early surgical intervention versus those suitable for observation has important implications for personalized and targeted management strategies in the era of precision medicine. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Human Papillomavirus Family (HPV) Induced Oncogenesis)

21 pages, 853 KiB

Open AccessReview

Human Papillomavirus Infection in Penile Cancer: Multidimensional Mechanisms and Vaccine Strategies

by Lichao Wei, Kangbo Huang, Hui Han and Ran-yi Liu

Int. J. Mol. Sci. 2023, 24(23), 16808; https://doi.org/10.3390/ijms242316808 - 27 Nov 2023

Cited by 2 | Viewed by 2227

Abstract

Penile cancer (PC) is a rare male malignant tumor, with early lymph node metastasis and poor prognosis. Human papillomavirus (HPV) plays a key role in the carcinogenesis of PC. This review aims to summarize the association between HPV infection and PC in terms [...] Read more.

Penile cancer (PC) is a rare male malignant tumor, with early lymph node metastasis and poor prognosis. Human papillomavirus (HPV) plays a key role in the carcinogenesis of PC. This review aims to summarize the association between HPV infection and PC in terms of virus–host genome integration patterns (the disrupted regions in the HPV and PC genome), genetic alterations, and epigenetic regulation (methylation and microRNA modification) occurring in HPV and PC DNA, as well as tumor immune microenvironment reprogramming. In addition, the potential of HPV vaccination strategies for PC prevention and treatment is discussed. Understanding of the HPV-related multidimensional mechanisms and the application of HPV vaccines will promote rational and novel management of PC. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Human Papillomavirus Family (HPV) Induced Oncogenesis)

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16 pages, 4759 KiB

Open AccessReview

Protein–DNA Interactions Regulate Human Papillomavirus DNA Replication, Transcription, and Oncogenesis

by Roxanne Evande, Anshul Rana, Esther E. Biswas-Fiss and Subhasis B. Biswas

Int. J. Mol. Sci. 2023, 24(10), 8493; https://doi.org/10.3390/ijms24108493 - 9 May 2023

Cited by 11 | Viewed by 4789

Abstract

Human papillomavirus (HPV) is a group of alpha papillomaviruses that cause various illnesses, including cancer. There are more than 160 types of HPV, with many being “high-risk” types that have been clinically linked to cervical and other types of cancer. “Low-risk” types of [...] Read more.

Human papillomavirus (HPV) is a group of alpha papillomaviruses that cause various illnesses, including cancer. There are more than 160 types of HPV, with many being “high-risk” types that have been clinically linked to cervical and other types of cancer. “Low-risk” types of HPV cause less severe conditions, such as genital warts. Over the past few decades, numerous studies have shed light on how HPV induces carcinogenesis. The HPV genome is a circular double-stranded DNA molecule that is approximately 8 kilobases in size. Replication of this genome is strictly regulated and requires two virus-encoded proteins, E1 and E2. E1 is a DNA helicase that is necessary for replisome assembly and replication of the HPV genome. On the other hand, E2 is responsible for initiating DNA replication and regulating the transcription of HPV-encoded genes, most importantly the E6 and E7 oncogenes. This article explores the genetic characteristics of high-risk HPV types, the roles of HPV-encoded proteins in HPV DNA replication, the regulation of transcription of E6 and E7 oncogenes, and the development of oncogenesis. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Human Papillomavirus Family (HPV) Induced Oncogenesis)

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