HPV16 E1 dysregulated cellular genes involved in cell proliferation and host DNA damage: A possible role in cervical carcinogenesis.
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ABSTRACT:
SUBMITTER: Baedyananda F
PROVIDER: S-EPMC8717967 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cervical cancer is the third most common cancer in women worldwide. Persistent infection with high-risk HPV types, principally HPV16 and 18 is the main risk factor for the development of this malignancy. However, the onset of invasive tumor occurs many years after initial exposure in a minority of infected women. This suggests that other factors beyond viral infection are necessary for tumor establishment and progression. Tumor progression is characterized by an increase in secretion and activation of matrix metalloproteinases (MMPs) produced by either the tumor cells themselves or tumor-associated fibroblasts or macrophages. Increased MMPs expression, including MMP-2, MMP-9 and MT1-MMP, has been observed during cervical carcinoma progression. These proteins have been associated with degradation of ECM components, tumor invasion, metastasis and recurrence. However, few studies have evaluated the interplay between HPV infection and the expression and activity of MMPs and their regulators in cervical cancer. We analyzed the effect of HPV16 oncoproteins on the expression and activity of MMP-2, MMP-9, MT1-MMP, and their inhibitors TIMP-2 and RECK in cultures of human keratinocytes. We observed that E7 expression is associated with increased pro-MMP-9 activity in the epithelial component of organotypic cultures, while E6 and E7 oncoproteins co-expression down-regulates RECK and TIMP-2 levels in organotypic and monolayers cultures. Finally, a study conducted in human cervical tissues showed a decrease in RECK expression levels in precancer and cancer lesions. Our results indicate that HPV oncoproteins promote MMPs/RECK-TIMP-2 imbalance which may be involved in HPV-associated lesions outcome.
| S-EPMC3306414 | biostudies-literature
Project description:A subset of the mucosotropic human papillomaviruses (HPV), including HPV16, are etiologic agents for the vast majority of cervical cancers, other anogenital cancers, and a subset of head and neck squamous cell carcinomas. HPV16 encodes three oncogenes: E5, E6, and E7. Although E6 and E7 have been well-studied and clearly shown to be important contributors to these cancers, less is known about E5. In this study, we used E5 transgenic mice to investigate the role of E5 in cervical cancer. When treated for 6 months with estrogen, a cofactor for cervical carcinogenesis, E5 transgenic mice developed more severe neoplastic cervical disease than similarly treated nontransgenic mice, although no frank cancers were detected. In addition, E5 when combined with either E6 or E7 induced more severe neoplastic disease than seen in mice expressing only one viral oncogene. Prolonged treatment of E5 transgenic mice with exogenous estrogen uncovered an ability of E5 to cause frank cancer. These data indicate that E5 acts as an oncogene in the reproductive tracts of female mice.
| S-EPMC2848882 | biostudies-literature
Project description:hnRNP E1 (heterogeneous nuclear ribonucleoprotein E1) is an important RNA-binding protein (RBPs) that plays a vital role in tumor development. Human papillomavirus 16 (HPV16) contains numerous sites that can bind to RNA/DNA and may be modified by multiple RBPs, which contribute to HPV gene expression and HPV-associated cancer development. However, the effects of hnRNP E1 on HPV16 oncogenes in the development of cervical lesions remain unclear. A total of 816 participants with different grades of cervical lesions were enrolled in a community-based cohort established in Shanxi Province, China. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to analyze the association between hnRNP E1 mRNA expression and cervical lesions. Cells with up_ and down_regulated hnRNP E1 were established. hnRNP E1 functions were evaluated using cell counting kit-8, flow cytometry analyses, and chromatin immunoprecipitation sequencing. Our results showed that hnRNP E1 expression was linearly dependent on the severity of the cervical lesions. Low expression of HPV16 E2, high expression of E6, and a low ratio of E2 to E6 could increase the risk of cervical lesions. hnRNP E1 expression was correlated with HPV16 oncogene expression. hnRNP E1-relevant genes were involved in the dopaminergic synapses, Wnt signaling pathway, gnRH secretion, and mTOR signaling pathway. hnRNP E1 significantly inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G0/G1 stage, and decreased HPV16 E6 expression. Our results indicate that hnRNP E1 could downregulate HPV16 E6 oncogene expression and inhibit cervical cancerization, which sheds new light on preventing the carcinogenicity of HPV across a range of diseases by regulating RNA-binding proteins.
| S-EPMC9253288 | biostudies-literature
Project description:Deregulated expression of viral E6 and E7 genes often caused by viral genome integration of high-risk human papillomaviruses (HR-HPVs) into host DNA and additional host genetic alterations are thought to be required for the development of cervical cancer. However, approximately 15% of invasive cervical cancer specimens contain only episomal HPV genomes. In this study, we investigated the tumorigenic potential of human cervical keratinocytes harboring only the episomal form of HPV16 (HCK1T/16epi). We found that the HPV16 episomal form is sufficient for promoting cell proliferation and colony formation of parental HCK1T cells. Ectopic expression of host oncogenes, MYC and PIK3CAE545K, enhanced clonogenic growth of both early- and late-passage HCK1T/16epi cells, but conferred tumor-initiating ability only to late-passage HCK1T/16epi cells. Interestingly, the expression levels of E6 and E7 were rather lower in late-passage than in early-passage cells. Moreover, additional introduction of a constitutively active MEK1 (MEK1DD) and/or KRASG12V into HCK1T/16epi cells resulted in generation of highly potent tumor-initiating cells. Thus an in vitro model for progression of cervical neoplasia with episomal HPV16 was established. In the model, constitutively active mutation of PIK3CA, PIK3CAE545K, and overexpression of MYC, in the cells with episomal HPV16 genome were not sufficient, but an additional event such as activation of the RAS-MEK pathway was required for progression to tumorigenicity.
| S-EPMC9916646 | biostudies-literature
Project description:Cervical cancer, induced by persistent HPV infection, has a high mortality rate. The E3 ubiquitin ligase Cullin 2 (CUL2) is critical for HPV16 E7-mediated degradation of retinoblastoma protein (pRb). Dysregulation of microRNAs (miRNAs) is induced during tumorigenesis; however, the association between miRNA networks and CUL2, specific to cervical cancer, remains unknown. Herein, we determined miRNA profiles in cervical cancer tissues using an Affymetrix miRNA array. We found that miR-154-5p was downregulated during cancer progression using real-time quantitative reverse transcription PCR in 130 biopsy specimens. Bioinformatics analysis and dual-luciferase reporter assays indicated that miR-154-5p directly targets the CUL2 3'UTR. To determine the functional consequences of modulating miR-154-5p and CUL2 levels, HPV16-positive cervical cancer cell line (SiHa) was transfected with miR-154-5p mimic, miR-154-5p inhibitor, or CUL2 siRNA. The proliferation, migration, and invasion of transfected cells were evaluated using CCK8 cell counting kit, wound-healing assay, and Transwell invasion assay. Increased miR-154-5p expression promoted significantly reduced SiHa cell proliferation, migration, and invasion, whereas the miR-154-5p inhibitor had the opposite effect. CUL2 silencing had similar effects to those of the miR-154-5p mimic. Consistent with the inverse correlation between miR-154-5p and CUL2 levels, CUL2 silencing also increased pRb expression. To our knowledge, this is the first study to demonstrate that miR-154-5p regulates pRb expression by targeting CUL2 3'UTR, thereby playing a tumor-suppressive role in HPV16 E7-induced cervical carcinogenesis.
| S-EPMC7391205 | biostudies-literature
Project description:MicroRNAs(miRNAs) have become the center of interest in oncology. In recent years, various studies have demonstrated that miRNAs regulate gene expression by influencing important regulatory genes and thus are responsible for causing cervical cancer. Cervical cancer being the third most diagnosed cancer among the females worldwide, is the fourth leading cause of cancer related mortality. Prophylactic human papillomavirus (HPV) vaccines and new HPV screening tests, combined with traditional Pap test screening have greatly reduced cervical cancer. Yet, thousands of women continue to be diagnosed with and die of this preventable disease annually. This has necessitated the scientists to ponder over ways of evolving new methods and chalk out novel treatment protocols/strategies. As miRNA deregulation plays a key role in malignant transformation of cervical cancer along with its targets that can be exploited for both prognostic and therapeutic strategies, we have collected and reviewed the role of miRNA in cervical cancer. A systematic search was performed using PubMed for articles that report aberrant expression of miRNA in cervical cancer. The present review provides comprehensive information for 246 differentially expressed miRNAs gathered from 51 published articles that have been implicated in cervical cancer progression. Of these, more than 40 miRNAs have been reported in the literature in several instances signifying their role in the regulation of cancer. We also identified 40 experimentally validated targets, studied the cause of miRNAs dysregulation along with its mechanism and role in different stages of cervical cancer. We also identified and analysed miRNA clusters and their expression pattern in cervical cancer. This review is expected to further enhance our understanding in this field and serve as a valuable reference resource.
| S-EPMC4133953 | biostudies-literature
Project description:Cervical intraepithelial neoplasia (CIN) is caused by human papillomavirus (HPV) infection and is the precursor to cervical carcinoma. The completion of the HPV productive life cycle depends on the expression of viral proteins which further determines the severity of the cervical neoplasia. Initiation of the viral productive replication requires expression of the E2 viral protein that cooperates with the E1 viral DNA helicase. A decrease in the viral DNA replication ability and increase in the severity of cervical neoplasia is accompanied by simultaneous elevated expression of E6 and E7 oncoproteins. Here we reveal a novel and important role for the HPV16-E2 protein in controlling host cell cycle during malignant transformation. We showed that cells expressing HPV16-E2 in vitro are arrested in prophase alongside activation of a sustained DDR signal. We uncovered evidence that HPV16-E2 protein is present in vivo in cells that express both mitotic and DDR signals specifically in CIN3 lesions, immediate precursors of cancer, suggesting that E2 may be one of the drivers of genomic instability and carcinogenesis in vivo.
| S-EPMC4741503 | biostudies-literature
Project description:It has been shown that HPV16 E7, but not other genotypes, can bind to scaffold protein CUL2 during inducing cervical carcinogenesis, but the expression level, associated regulating mechanism, and potential carcinogenicity of CUL2 itself is still unknown as yet. Here, we demonstrated that CUL2 was specifically overexpressed in HPV16 positive cervical cancer cells and tissues, and CUL2 expression was significantly increased along with the cervical lesion progression and positively correlated with HPV16 E7. CUL2 knockdown slowed the growth of xenograft tumors in mouse models. Importantly, CUL2 specifically bound to HPV16 E7, but not HPV18 E7. Moreover, CUL2 acted as a direct target of miR-424, and reversely suppressed miR-424; E2F transcription factor 1 (E2F1) suppressed miR-424 expression; CUL2 bound to E2F1 and promoted E2F1 expression. Our results indicate the existence of a regulatory loop among CUL2, E2F1, and miR-424 in HPV16 positive cervical cancer cells. Our results suggest that E7 recruited CUL2, driven by CUL2/E2F1/miR-424 regulatory loop, is overexpressed and accelerates HPV16-induced cervical carcinogenesis. Our findings may serve as one of the explanations for a clinical phenomenon that HPV16 possesses the strongest cervical carcinogenicity among high-risk HPV genotypes.
| S-EPMC5058775 | biostudies-literature
Project description:BackgroundHuman papillomavirus (HPV) type 16 accounts for a larger share of cervical cancer and has been a major health problem worldwide for decades. The progression of initial infection to cervical cancer has been linked to viral sequence properties; however, the role of HPV16 variants in the risk of cervical carcinogenesis, especially with longitudinal follow-up, is not fully understood in China.MethodsWe aimed to investigate the genetic variability of HPV16 E6 and E7 oncogenes in isolates from cervical exfoliated cells. Between December 2012 and December 2014, a total of 310 single HPV16-positive samples were selected from women living in the Taizhou area, China. Sequences of all E6 and E7 oncogenes were analysed by PCR-sequencing assay. Detailed sequence comparison, genetic heterogeneity analyses and maximum-likelihood phylogenetic tree construction were performed with BioEdit Sequence Alignment Editor and MEGA X software. Data for cytology tests and histological diagnoses were obtained from our Taizhou Area Study with longitudinal follow-up for at least 5 years. The relationship between HPV16 variants and cervical carcinogenesis risk was analysed by the chi-square test or Fisher's exact test.ResultsIn this study, we obtained 64 distinct variation patterns with the accession GenBank numbers MT681266-MT681329. Phylogenetic analysis revealed that 98.3% of HPV16 variants belong to lineage A, in which the A4 (Asian) sublineage was dominant (64.8%), followed by A2 (12.1%), A1 (11.4%), and A3 (10.0%). The A4 (Asian) sublineage had a higher risk of CIN2+ than the A1-3 (European) sublineages (OR = 2.69, 95% CI = 1.04-6.97, P < 0.05). Furthermore, nucleotide variation in HPV16 E6 T178G is associated with the development of cervical cancer.ConclusionThese data could provide novel insights into the role of HPV16 variants in cervical carcinogenesis risk in China.
| S-EPMC8254333 | biostudies-literature
Project description:Central to the recognition, signaling, and repair of DNA double-strand breaks (DSBs) are the MRE11-RAD50-NBS1 (MRN) complex and mediator of DNA damage checkpoint protein 1 (MDC1), the interplay of which is essential for initiation and amplification of the DNA damage response (DDR). The intrinsic rule governing the regulation of the function of this molecular machinery remains to be investigated. We report here that the ubiquitin-specific protease USP7 was physically associated with the MRN-MDC1 complex and that the MRN-MDC1 complex acted as a platform for USP7 to efficiently deubiquitinate and stabilize MDC1, thereby sustaining the DDR. Accordingly, depletion of USP7 impaired the engagement of the MRN-MDC1 complex and the consequent recruitment of the downstream factors p53-binding protein 1 (53BP1) and breast cancer protein 1 (BRCA1) at DNA lesions. Significantly, USP7 was overexpressed in cervical cancer, and the level of its expression positively correlated with that of MDC1 and worse survival rates for patients with cervical cancer. We demonstrate that USP7-mediated MDC1 stabilization promoted cervical cancer cell survival and conferred cellular resistance to genotoxic insults. Together, our study reveals a role for USP7 in regulating the function of the MRN-MDC1 complex and activity of the DDR, supporting the pursuit of USP7 as a potential therapeutic target for MDC1-proficient cancers.
| S-EPMC6159995 | biostudies-literature