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The antigen processing-associated transporter gene polymorphism: Role on gene and protein expression in HPV-infected pre-cancerous cervical lesion.

ABSTRACT: Human papillomavirus (HPV) is the major pathogen for cervical lesions. The evasion mechanism of the immune response and persistence of HPV infection can be influenced by polymorphisms (SNPs) in genes associated with transporter associated with antigen processing (TAP), which may change the peptide binding affinity or the TAP expression impacting the efficiency of peptide transport in the secretory pathway, and the presentation of peptides to cytotoxic T lymphocytes. This study aimed to evaluate the role of the TAP1 and TAP2 polymorphisms, TAP1, and TAP2 genes expressions, and protein levels in cervical cells presenting different degrees of pre-cancerous lesions in 296 immunocompetent women infected or not by HPV. TAP SNPs were genotyped by Sanger sequencing, and gene expression by real-time PCR. Aneuploidy was determined by DNA index using flow cytometry. TAP-1 and TAP-2 tissue expressions were evaluated by immunohistochemistry. The Asp697Gly SNP of TAP1 presented a risk for cellular aneuploidy (P=0.0244). HPV+ women had higher TAP-2 mRNA (P=0.0212) and protein (P<0.0001) levels. The TAP2D and TAP2E haplotypes were associated with the risk for aneuploidy and pre-cancerous lesions. In conclusion, nucleotide variability at the peptide binding region of peptide transporter genes, particularly of the TAP2 gene, may influence the HPV-peptide transportation from the cytosol to the endoplasmic reticulum, increasing the susceptibility to the development of high-grade cervical lesions.

SUBMITTER: Medeiros FS

PROVIDER: S-EPMC9811671 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The antigen processing-associated transporter gene polymorphism: Role on gene and protein expression in HPV-infected pre-cancerous cervical lesion.

Medeiros Fernanda Silva FS da Silva Mauro César MC da Silva Neila Caroline Henrique NCH Gomes Thailany Thays TT Gomes Renan Garcia RG Paiva Larissa Albuquerque LA Dos Santos Gomes Fabiana Oliveira FO Peixoto Christina Alves CA Rygaard Maria Carolina Valença MCV Welkovic Stefan S Menezes Maria Luiza Bezerra MLB Donadi Eduardo Antônio EA Lucena-Silva Norma N

Frontiers in cellular and infection microbiology 20221221

Human papillomavirus (HPV) is the major pathogen for cervical lesions. The evasion mechanism of the immune response and persistence of HPV infection can be influenced by polymorphisms (SNPs) in genes associated with transporter associated with antigen processing (TAP), which may change the peptide binding affinity or the TAP expression impacting the efficiency of peptide transport in the secretory pathway, and the presentation of peptides to cytotoxic T lymphocytes. This study aimed to evaluate ...[more]

PMID: 36619767

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Project description:As the fourth most common gynecological cancer, cervical cancer has resulted in more than 300,000 deaths worldwide in 2020. The expression of the human papillomavirus (HPV) oncogenes E6 and E7 is significantly involved in the initiation and progression of cervical neoplasia. Additionally, the composition of the vaginal microbiome was also closely associated with the ability of HPV to induce cervical cancer. However, the relationship between the expression of HPV E6/E7 oncogene and the composition of the vaginal microbiome has not been clearly explored. In our present study, to investigate the relationship between the HPV E6/E7 oncogene and vaginal microbiome, cervical swabs from 115 patients were collected, and their vaginal microbiomes were analyzed by using metagenomics sequencing. Along with the progression of cervical lesions, the diversity of cervical flora increased gradually, and the abundance of Lactobacillus decreased. Compared with the HPV group, the prevalence of HPV E6/E7 and oncogene expression level were significantly upregulated in cervical intraepithelial neoplasia (CIN) and cervical cancer (CC) groups. Additionally, a positive correlation between the expression of the HPV oncogene and the genera Sneathia, Salmonella, Leptotrichia, Pseudomonas, and Roseovarius in the HPV group was observed. In the CIN group, the enrichment of the genera Sneathia and Megasphaera was weakly linked with HPV oncogene overexpression. In the CC group, a strong association between the overabundance of the genera Peptostreptococcus and Enterococcus and the high expression of HPV oncogene was also found. The increased diversity of the vaginal microbiota and the decreased Lactobacillus abundance were significantly associated with the severity of cervical disease, and the expression of the HPV oncogene could also be regulated by certain pathogens in different stages of cervical lesions. IMPORTANCE The main findings of this study were that we clarified the associations of the different bacterial species with the expression of human papillomavirus (HPV) oncogenes at different stages of cervical cancer. Along with the severity of cervical lesions, the abundance of the genus and species of Lactobacillus obviously declined, while the aerobic and anaerobic bacteria, as well as the prevalence and expression of HPV E6/E7 oncogene, were increased dramatically.

Project description:BackgroundCervical cancer is a preventable disease if treated early, but remains the second leading cause of cancer-related mortality among women in low and middle-income countries. Data on epidemiology and risk factors in these settings are scarce. This study aimed to assess the prevalence of pre-cancerous cervical lesions and risk factors in Tigray region, Ethiopia.MethodsA community-based, cross-sectional study was used and 900 participants were 30 recruited using multistage sampling and finally data from 883 were collected using an interviewer administered questionnaire and screening with visual inspection with ascetic acid. Data were collected using an interviewer administered questionnaire and screening with visual inspection with acetic acid from March 2016 to June 2017. Multinomial logistic regression analysis was conducted to estimate predictors.ResultsSeventy-nine (8.95%) women were positive for pre-cancer lesion and 35 (3.96%) were suspicious for cervical cancer. We used relative risk ratio (rrr) to estimate the strength of association. Divorced or widowed women had 2.5 and 4.7 times more risk of being positive and suspicious respectively, compared to single women (rrr = 2.5, 95% CI [1.13, 5.52]); (rrr = 4.69, 95% CI [1.00, 21.84]). The risk of having a suspicious result was 68% lower for women with primary education compared to those with no formal education (rrr = 0.32, 95% CI [1.00, 21.84]). History of sexually transmitted infection was associated with positive pre cancer lesion (rrr = 1.91, 95% CI [1.11, 3.27]) whereas, being farmer (rrr = 4.83, 95% CI [1.44, 16.13]), merchant (rrr = 4.85, 95% CI [1.52, 15.46]), bleeding between periods (rrr = 3.26, 95% CI [1.32, 8.04]) and pelvic or back pain (rrr = 2.79, 95% CI [1.18, 6.58]) were associated with suspicious for cancer.ConclusionAbout 8.9% and 3.96% of the women were positive for pre-cancerous cervical lesion and suspicious for cancer, respectively. The prevalence of pre-cancerous cervical lesion is high as compared to other regional prevalence in the country. Marital status, education, sexually transmitted infection, bleeding, and pelvic pain were risk factors of pre-cancerous cervical lesion'. This finding implies that the sexual exposure, having no permanent husband and being not educated attributes to the high prevalence of pre-cancerous cervical lesion and may aggravate the transmission of HPV."

Project description:BackgroundOncogene-Induced Senescence (OIS) is a form of senescence that occurs as a consequence of oncogenic overstimulation and possibly infection by oncogenic viruses. Whether senescence plays a role in the pathogenesis of cervical cancer (CC) is not well understood. Moreover, whether cervical epithelial cells that are part of the premalignant cervical intraepithelial neoplasia (CIN), exhibit markers of OIS in Human Papillomavirus (HPV)-infected tissue, has not been investigated.MethodsWe utilized a set of patient-derived premalignant and malignant tissue samples to investigate the protein (Ki67 and Lamin B1) and gene (TP53, IL1A, CCL2, and MMP9) expression of several OIS-associated biomarkers using immunohistochemistry (IHC) and qRT-PCR, respectively. Furthermore, we characterized the HPV status of all tissue samples.ResultsMost of the CC samples (34/37) were positive for HPV, mainly HPV-16 which was observed in 62.2% of the CC samples. Among CINs, HPV infection was found in 60.2% of the 32 samples with HPV-16 as the dominant genotype in 58.5% of the CINs. IHC analysis revealed a significant increase in the expression levels of both Ki67 and Lamin B1 proteins in CC tissue compared to CIN. On average, 93% of tumor cells were positive for Ki67 in comparison to only 25% of premalignant cells in CIN samples. Similarly, Lamin B1 expression was observed in 89% of tumor cells in malignant tissue on average, compared to 60% in CIN samples. Importantly, Lamin B1 expression was elevated in nonmalignant cervical tissue suggesting that its downregulation is more predominant in the premalignant state. Furthermore, RT-PCR revealed a significant decrease in the expression of TP53, IL1a, CCL2, and MMP9 markers in CC samples compared to CINs. Specifically, 84% of CC samples showed reduced TP53 expression, 90% showed reduced IL1a expression, 74% showed reduced CCL2 expression, and 76% showed reduced MMP9 expression when compared with their premalignant baseline. Infection of HPV was confirmed in 61% of the tumor tissues while only 25% of the CINs were positive for HPV.ConclusionThis work shall provide an opportunity to further examine the role of OIS in the process of HPV-driven CC development.

Dataset Information

The antigen processing-associated transporter gene polymorphism: Role on gene and protein expression in HPV-infected pre-cancerous cervical lesion.

Publications

The antigen processing-associated transporter gene polymorphism: Role on gene and protein expression in HPV-infected pre-cancerous cervical lesion.

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