RESUMEN
OBJECTIVE: To identify differentially expressed long noncoding RNAs (lncRNAs) in condyloma acuminatum (CA) and to explore their probable regulatory mechanisms by establishing coexpression networks. METHODS: High-throughput RNA sequencing was performed to assess genome-wide lncRNA expression in CA and paired adjacent mucosal tissue. The expression of candidate lncRNAs and their target genes in larger CA specimens was validated using real-time quantitative reverse transcriptase polymerase chain reaction (RTâqPCR). Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for the functional enrichment analysis of these candidate lncRNAs and differential mRNAs. The coexpressed mRNAs of the candidate lncRNAs, calculated by Pearson's correlation coefficient, were also analysed using GO and KEGG analysis. In addition, the interactions among differentially expressed lncRNAs (DElncRNAs)-cis-regulatory transcription factors (cisTFs)-differentially expressed genes (DEGs) were analysed and their network was constructed. RESULTS: A total of 546 lncRNAs and 2553 mRNAs were found to be differentially expressed in CA compared to the paired control. Functional enrichment analysis revealed that the DEGs coexpressed with DElncRNAs were enriched in the terms of cell adhesion and keratinocyte differentiation, and the pathways of ECM-receptor interaction, local adhesion, PI3K/AKT and TGF-ß signaling. We further constructed the network among DElncRNAs-cisTFs-DEGs and found that these 95 DEGs were mainly enriched in GO terms of epithelial development, regulation of transcription or gene expression. Furthermore, the expression of 3 pairs of DElncRNAs and cisTFs, EVX1-AS and HOXA13, HOXA11-AS and EVX1, and DLX6-AS and DLX5, was validated with a larger number of specimens using RTâqPCR. CONCLUSION: CA has a specific lncRNA profile, and the differentially expressed lncRNAs play regulatory roles in mRNA expression through cis-acting TFs, which provides insight into their regulatory networks. It will be useful to understand the pathogenesis of CA to provide new directions for the prevention, clinical treatment and efficacy evaluation of CA.
Asunto(s)
Condiloma Acuminado , Redes Reguladoras de Genes , ARN Largo no Codificante , ARN Largo no Codificante/genética , Humanos , Condiloma Acuminado/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Perfilación de la Expresión Génica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Masculino , Ontología de Genes , Femenino , AdultoRESUMEN
Background: Condyloma acuminatum (CA) is caused by low-risk human papillomavirus, and is characterized by high recurrence after treatment. The RNA modification N6-methyladenosine (m6A) plays an important role during diverse viral infections, including high-risk HPV infection in cervical cancer. However, it is unclear whether low-risk HPV infection changes the RNA m6A methylation in CA. Methods: High-throughputm6A-sequencing was performed to profile the transcriptome-wide mRNA modifications of CA tissues infected by LR-HPVs and the paired normal tissues from CA patients. We further investigated the regulation of alternative splicing by RNA binding proteins (RBPs) with altered m6A modification and constructed a regulatory network among these RBPs, regulated alternative splicing events (RASEs) and regulated alternative splicing genes (RASGs) in CA. Results: The results show that the m6A level in CA tissues differed from that in the paired controls. Furthermore, cell cycle- and cell adhesion- associated genes with m6A modification were differentially expressed in CA tissues compared to the paired controls. In particular, seven RNA binding protein genes with specific m6A methylated sites, showed a higher or lower expression at the mRNA level in CA tissues than in the paired normal tissues. In addition, these differentially expressed RNA binding protein genes would regulate the alternative splicing pattern of apoptotic process genes in CA tissue. Conclusions: Our study reveals a sophisticated m6A modification profile in CA tissue that affects the response of host cells to HPV infection, and provides cues for the further exploration of the roles of m6A and the development of a novel treatment strategy for CA.
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Empalme Alternativo , Condiloma Acuminado , Proteínas de Unión al ARN , Humanos , Empalme Alternativo/genética , Condiloma Acuminado/genética , Condiloma Acuminado/virología , Condiloma Acuminado/metabolismo , Condiloma Acuminado/patología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Femenino , Adenosina/análogos & derivados , Adenosina/metabolismo , Metilación , Adulto , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transcriptoma , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/patología , Metilación de ARNRESUMEN
Condyloma acuminatum (CA) is a prevalent sexually transmitted disease caused by low-risk human papillomavirus infection, characterized by high transmission and recurrence rates. Long non-coding RNAs (lncRNAs) play a crucial role in regulating gene transcription and are involved in various biological processes. Although recent studies have demonstrated the involvement of lncRNAs in cervical cancer, their expression profile and function in CA remain poorly understood. In this study, we aimed to identify messenger RNA (mRNA) and lncRNA expression patterns in CA using high-throughput lncRNA sequencing. We found that 3033 differentially expressed genes (DEGs) and 1090 differentially expressed lncRNAs (DELs) were significantly altered in CA compared to healthy controls. The results from quantitative reverse transcription polymerase chain reaction and immunohistochemical staining are in accordance with the observed trends in the sequencing data. Functional enrichment analysis revealed that upregulated DEGs in CA were involved in biological processes such as virus response, immune response, cell cycle regulation, the tumor necrosis factor signaling pathway, and the P53 signaling pathway. Co-expression network analysis identified potential target genes of DELs, with enrichment in biological processes such as cell differentiation, the intrinsic apoptotic signaling pathway, and pathways such as virus infection, pathways in cancer, T helper 17 cell differentiation, the mitogen-activated protein kinase signaling pathway, and the Wnt signaling pathway. Collectively, our findings indicate significant changes in the transcriptome profile, including mRNAs and lncRNAs, in CA compared to healthy controls. Our study provides new insights into the potential functions of lncRNAs in the pathogenesis of CA and identifies potential therapeutic targets for this disease.
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Condiloma Acuminado , Perfilación de la Expresión Génica , ARN Largo no Codificante , ARN Mensajero , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/metabolismo , ARN Mensajero/genética , Condiloma Acuminado/genética , Condiloma Acuminado/virología , Femenino , Masculino , Adulto , Redes Reguladoras de Genes , Estudios de Casos y Controles , Persona de Mediana EdadRESUMEN
Condyloma acuminata (CA) is a benign proliferative disease mainly affecting in non-keratinized epithelia. Most cases of CA are caused by low-risk human papillomavirus (HPV), mainly HPV 6 and 11. The aim of the current study was to highlight the candidate genes and pathways associated with immune alterations in individuals who did not spontaneously eliminate the virus and, thus, develop genital warts. Paraffin-embedded condyloma samples (n = 56) were analyzed by immunohistochemistry using antibodies against CD1a, FOXP3, CD3, CD4, CD8, and IFN-γ. The immunomarkers were chosen based on the evaluation of the innate and adaptive immune pathways using qPCR analysis of 92 immune-related genes, applying a TaqMan Array Immune Response assay in HPV 6 or HPV 11 positive samples (n = 27). Gene expression analysis revealed 31 differentially expressed genes in CA lesions. Gene expression validation revealed upregulation of GZMB, IFNG, IL12B, and IL8 and downregulation of NFATC4 and IL7 in CA samples. Immunohistochemical analysis showed increased FOXP3, IFN-γ, CD1a, and CD4 expression in CA than in the control tissue samples. In contrast, CD3 and CD8 expression was decreased in CA lesion samples. Increased levels of pro-inflammatory cytokines in HPV-positive patients compared with HPV-negative patients seem to reflect the elevated immunogenicity of HPV-positive CA lesions. Host defense against HPV begins during the early stages of the innate immune response and is followed by activation of T lymphocytes, which are mainly represented by CD4+ and regulatory T cells. The low CD8+ T cell count in CA may contribute to this recurrent behavior. Additional studies are needed to elucidate the mechanism of host defense against HPV infection in CA.
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Condiloma Acuminado , Infecciones por Papillomavirus , Humanos , Infecciones por Papillomavirus/genética , Condiloma Acuminado/genética , Condiloma Acuminado/patología , Citocinas , Inmunidad , Factores de Transcripción Forkhead/genética , Papillomaviridae/genéticaAsunto(s)
Condiloma Acuminado/genética , Condiloma Acuminado/virología , Papillomaviridae/genética , Adolescente , Niño , Preescolar , Femenino , Genotipo , Alemania , Humanos , Lactante , MasculinoRESUMEN
OBJECTIVE: Investigate the role of Yes-associated protein (YAP1) in the development of condyloma acuminatum (CA). METHODS: We enrolled 30 male patients with CA and 20 healthy individuals as a control group, to compare the YAP1 expression in their tissue samples. Following this, we overexpressed and downregulated YAP1 expression in HaCaT cells to examine the migratory, proliferative, and apoptotic potential of HaCaT cells expressing different levels of YAP1. RESULTS: In the CA patient tissue samples, an increase in YAP1 expression can be observed. In vitro,the overexpression of YAP1 was shown to promote the growth and migration of HaCaT cells and to activate epidermal growth factor receptor (EGFR) pathway-associated proteins, while the downregulation of YAP1 inhibited cell growth and migration of these cells. CONCLUSIONS: YAP1 promotes the growth of keratinocytes in CA through the activation of the EGFR pathway, and it may mediate the development of human papilloma virus-associated diseases.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proliferación Celular , Condiloma Acuminado/metabolismo , Epidermis/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Apoptosis , Estudios de Casos y Controles , Movimiento Celular , Condiloma Acuminado/genética , Condiloma Acuminado/fisiopatología , Regulación hacia Abajo , Receptores ErbB/metabolismo , Silenciador del Gen , Células HaCaT , Humanos , Masculino , Persona de Mediana Edad , Transducción de Señal , Factores de Transcripción/genética , Transfección , Regulación hacia Arriba , Proteínas Señalizadoras YAPRESUMEN
ABSTRACT Host immunogenetic setting is involved in the regulation of human papillomavirus (HPV) infection and development of condyloma acuminatum (CA). We investigated the correlation of two common single nucleotide polymorphisms (SNPs) (−607C/A and −137G/C) of IL-18 with the susceptibility of CA in a large Chinese cohort. Out of 408 CA patients analyzed, 300 had HPV infection transmitted through sexual contact (SC) and 108 through non-sexual contact (NSC). In addition, 360 healthy volunteers were enrolled as controls. SNPs at positions −607C/A and −137G/C in IL-18 promoter were analyzed. Comparing CA patients to healthy controls, no dominant relevance was found between the IL-18 promoter −607 C/A or −137G/C polymorphisms and the CA disease either identified genotypically (p > 0.05) or by allelically (p > 0.05). However, the IL-18 promoter −137G/C polymorphism genotype and allele frequencies in the NSC CA group, but not between in the SC group, were significantly higher than in the controls. There was no dominant relevance between IL-18-607C/A polymorphism genotype and allele frequencies among SC, NSC CA patients, and controls. Our study demonstrates that polymorphism −137G/C in IL-18 promoter is significantly correlated with risk of CA in NSC patients.
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Humanos , Masculino , Femenino , Condiloma Acuminado/genética , Interleucina-18/genética , Polimorfismo de Nucleótido Simple/genética , Infecciones por Papillomavirus/complicaciones , Polimorfismo Genético , Condiloma Acuminado/virología , China , Estudios de Cohortes , Regiones Promotoras Genéticas , Predisposición Genética a la Enfermedad , Infecciones por Papillomavirus/transmisión , Pueblo Asiatico/genética , Alelos , GenotipoRESUMEN
Host immunogenetic setting is involved in the regulation of human papillomavirus (HPV) infection and development of condyloma acuminatum (CA). We investigated the correlation of two common single nucleotide polymorphisms (SNPs) (-607C/A and -137G/C) of IL-18 with the susceptibility of CA in a large Chinese cohort. Out of 408 CA patients analyzed, 300 had HPV infection transmitted through sexual contact (SC) and 108 through non-sexual contact (NSC). In addition, 360 healthy volunteers were enrolled as controls. SNPs at positions -607C/A and -137G/C in IL-18 promoter were analyzed. Comparing CA patients to healthy controls, no dominant relevance was found between the IL-18 promoter -607 C/A or -137G/C polymorphisms and the CA disease either identified genotypically (pâ¯>â¯0.05) or by allelically (pâ¯>â¯0.05). However, the IL-18 promoter -137G/C polymorphism genotype and allele frequencies in the NSC CA group, but not between in the SC group, were significantly higher than in the controls. There was no dominant relevance between IL-18-607C/A polymorphism genotype and allele frequencies among SC, NSC CA patients, and controls. Our study demonstrates that polymorphism -137G/C in IL-18 promoter is significantly correlated with risk of CA in NSC patients.
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Condiloma Acuminado/genética , Interleucina-18/genética , Infecciones por Papillomavirus/complicaciones , Polimorfismo de Nucleótido Simple/genética , Alelos , Pueblo Asiatico/genética , China , Estudios de Cohortes , Condiloma Acuminado/virología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Infecciones por Papillomavirus/transmisión , Polimorfismo Genético , Regiones Promotoras GenéticasRESUMEN
BACKGROUND: Condylomata acuminata are benign anogenital warts caused by human papillomavirus (HPV) infection with a high recurrence rate. Autophagy plays an important role in maintaining internal environmental stability. However, the role of autophagy regulation in the anogenital warts caused by HPV infection remains unknown. OBJECTIVE: A multigroup case-control study was designed to identify the autophagy gene fingerprint involved in anogenital warts arising from infections with different HPV genotypes. METHODS: Human autophagy PCR arrays were performed on the initial 18 participants grouped by their different HPV genotypes for gene expression-profiling analysis. The negative control was skin samples collected during plastic surgery on the chest from a group of individuals who showed none of the clinical symptoms or evidence of HPV infection. Real-time polymerase chain reaction (qPCR) was performed to validate the microarray results in another 24 individuals. RESULTS: Out of 84 genes involved in autophagy, different autophagic responses were found among the 29 genes that encode autophagy machinery components, and expression levels of 13 of these genes were downregulated. Finally, we verified that the expression levels of 2 key genes that participate in the formation of autophagosomes, ATG3 and -BECLIN1, were downregulated in the HPV infection groups independently of genotype compared with the control group. CONCLUSIONS: These findings showed that HPV infection downregulated the expression of ATGs in CA. Additionally, there were no differences in the expression of ATGs between the different HPV genotype infection groups. This study provided new insights into the autophagic response to HPV infection.
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Autofagia/genética , Condiloma Acuminado/genética , Papillomaviridae/genética , Infecciones por Papillomavirus/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , ADN Viral/genética , Regulación hacia Abajo , Femenino , Regulación Viral de la Expresión Génica , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The prevalence, clinical significance, and spectrum of many HPV genotypes are currently largely untapped. We report a case of anal condyloma associated with a rare HPV genotype in a 11-year-old kidney transplant recipient. Eleven months post-graft, rectal bleeding revealed a 5-cm-large anal condyloma for which immuno-histopathology revealed typical papillomatosis. HPV genotyping performed on anal biopsy identified a HPV type 7, for which a single sequence was found in the GenBank sequence database. HPV7 is classically found in hand cutaneous warts, but HPV7-associated condyloma was only described in two patients. Total resection of the anal lesion was performed by electrocoagulation with no recurrence after 6 years. Post-transplant immunosuppression may promote anal condyloma with uncommon HPV types. HPV genotyping in such lesions is useful to get a better understanding of the epidemiology and clinical significance of such unusual HPV types as HPV7.
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Enfermedades del Ano/virología , Condiloma Acuminado/virología , Trasplante de Riñón , Infecciones por Papillomavirus/virología , Enfermedades del Ano/genética , Enfermedades del Ano/inmunología , Niño , Condiloma Acuminado/genética , Condiloma Acuminado/inmunología , Humanos , Terapia de Inmunosupresión/métodos , Masculino , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/inmunologíaRESUMEN
BACKGROUND: Ingenol mebutat (IM)-gel is effective for the topical treatment of epithelial tumors, including actinic keratoses (AKs) or anogenital warts (AGW). AK patients treated with IM develop intensified inflammatory reactions on sights of prior clinical visible or palpable AKs as compared to the surrounding actinically damaged skin, suggesting the induction of a tumor cell-directed inflammation. AGW patients treated with IM develop even stronger inflammatory reactions with large erosions, suggesting a directed inflammatory response against HPV-infected keratinocytes. Of note, even widespread erosions heal very fast without any superinfections. Here, we set out to elucidate underlying molecular and cellular mechanisms of these clinical observations. METHODS: The effects of IM (10-9-10-5 M) on the expression and translation of a comprehensive set of chemokines (CXCL1, CXCL8, CXCL9, CXCL10, CXCL11, CXCL14, CCL2, CCL5, CCL20, CCL27) and antimicrobial peptides (AMP) (HBD1, HBD2, HBD3, LL37, RNase7) were analyzed in primary human epithelial keratinocytes (HEK) and a set of epithelial cancer cell lines by RT-qPCR and ELISA in vitro. To study the possible effects of different concentrations of IM on migratory, respectively wound healing responses, an in vitro scratch assay was conducted on HEK. RESULTS: Ingenol mebutat significantly and dose-dependently induced the expression of proinflammatory chemokines (CXCL8, CCL2) and AMP (RNase7, HBD3) in HEK and epithelial cancer cell lines. A significantly stronger induction of CXCL8 and CCL2 was observed in our tested tumor cells as compared to HEK. We did not observe any significant effect of IM on HEK migration, respectively wound healing responses in vitro for any tested concentration (10-9, 10-8, 10-6 M) except 10-7 M, which induced a significant inhibition. CONCLUSIONS: Our data suggest that tumor cells are more susceptible to IM as compared to differentiated HEK. This is evident by a stronger IM-mediated induction of proinflammatory chemokines in tumor cells, which may result in a tumor cell-directed inflammatory response and rapid tumor destruction. In addition, IM induces AMP in keratinocytes and seems not to severely interfere with keratinocyte migration, which contributes to a fast and uncomplicated wound healing. Surprising is a selective inhibition of keratinocyte migration by IM at the concentration of 10-7 M pointing to very dose depending biological effects, induced by IM.
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Condiloma Acuminado/tratamiento farmacológico , Diterpenos/farmacología , Inflamación/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Administración Tópica , Péptidos Catiónicos Antimicrobianos/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimiocinas/genética , Condiloma Acuminado/genética , Condiloma Acuminado/virología , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Inflamación/genética , Inflamación/virología , Queratinocitos/efectos de los fármacos , Queratinocitos/virología , Queratosis Actínica/tratamiento farmacológico , Queratosis Actínica/genética , Queratosis Actínica/virología , Neoplasias/genética , Neoplasias/virología , Papillomaviridae/efectos de los fármacos , Papillomaviridae/patogenicidad , Cicatrización de Heridas/efectos de los fármacos , Cicatrización de Heridas/genéticaRESUMEN
BACKGROUND: Hyperthermia is an effective treatment against cancer and human papillomavirus (HPV) infection. Previous studies have shown that heat shock proteins are crucial to the action of hyperthermia. OBJECTIVES: To examine the effects of hyperthermia in combination with DNAJA4-deficiency on human keratinocytes and Condyloma acumunatum (CA) tissues. METHODS: HaCaT cells were subjected to 44°C (compared to 37°C) waterbath for 30min for stimulation. Foreskin or CA tissues obtained from patients undergoing circumcision or pathological examination were bisected and subjected to similar treatments. DNAJA4-knockout (KO) HaCaT cells were generated with CRISPR/Cas9 technology. mRNA and protein expressions were determined using rt-qPCR and western-blotting. Cell cycle distribution, apoptosis and senescence were analyzed by flow cytometry. RESULTS: DNAJA4 was induced in HaCaT cells, foreskin and CA tissues subjected to hyperthermia at both transcriptional and translational levels. NF-kB,3 was activated by hyperthermia in HaCaT cells, and further enhanced by DNAJA4-deficiency. Transcription of TNF-α4; IL-1B,5 TNFAIP36 and IL-87 were induced in HaCaT cells subjected to hyperthermia. DNAJA4-knockout promoted transcriptions of TNF-α and IL-1B, whereas decreased that of TNFAIP3 and IL-8. Reduced cell survival, proliferation and viability were demonstrated using flow cytometry and MTS assays. Furthermore, NF-kB inhibitors reversed most of the phenotypes observed. CONCLUSIONS: Hyperthermia reduced HaCaT cell proliferation and promoted cytokine expressions responsible for anti-viral activity, mainly through a NF-kB dependent pathway. DNAJA4-deficiency enhanced the activation of NF-kB by hyperthermia in HaCaT cells, indicating that DNAJA4 may be a promising therapeutic target for use in the treatment of cutaneous HPV infections.
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Puntos de Control del Ciclo Celular , Proliferación Celular , Condiloma Acuminado/metabolismo , Proteínas del Choque Térmico HSP40/deficiencia , Respuesta al Choque Térmico , Hipertermia Inducida , Queratinocitos/metabolismo , FN-kappa B/metabolismo , Línea Celular , Senescencia Celular , Condiloma Acuminado/genética , Condiloma Acuminado/patología , Condiloma Acuminado/virología , Citocinas/metabolismo , Proteínas del Choque Térmico HSP40/genética , Interacciones Huésped-Patógeno , Humanos , Queratinocitos/patología , Queratinocitos/virología , Transducción de SeñalRESUMEN
Objective Condyloma acuminatum (CA) is a common, viral, sexually transmitted disease worldwide. Human papillomavirus (HPV) genotyping has important clinical implications for the treatment of CA. We developed a loop-mediated isothermal amplification (LAMP) method for the detection of HPV. Methods We collected 294 cervical scrape samples, including 30 HPV-6-positive, 30 HPV-11-positive, 22 HPV-16-positive, 20 HPV-42-positve, 30 HPV-43-positive, 20 HPV-44-positive and 142 HPV-negative samples. Tissues from 40 patients with a pathological diagnosis of CA were paraffin-embedded and analyzed by LAMP and Luminex. Hydroxynaphthol blue (HNB) and electrophoresis were used to detect the results of LAMP. Results LAMP and Luminex systems were compared in detecting six subtypes of HPV. LAMP reactions were specific for each subtype. The sensitivity of LAMP for HPV-6, as determined by the HNB indicator assay, was 1000 copies/tube. The kappa value between the two methods was 0.98 (HPV-6), 0.94 (HPV-11), 0.89 (HPV-43), 0.87 (HPV-42) 0.79 (HPV-16) and 0.68 (HPV-44). Among the 142 HPV-negative samples determined by the Luminex assay, HPV-6 was detected in eight and HPV-11 in one by LAMP. Among the 40 CA samples, the results of LAMP and Luminex were in agreement in 38 (95%). Conclusion The results of this study indicated that the LAMP assay with HNB is superior to the Luminex method in terms of sensitivity and specificity. The specificity of LAMP was 100% and the sensitivity of LAMP was 1000 copies/tube using HNB. LAMP is therefore a useful, quick and accurate method for the clinical diagnosis of HPV subtypes.
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Condiloma Acuminado/genética , Técnicas de Genotipaje/métodos , Papillomaviridae/genética , Adulto , Condiloma Acuminado/patología , Condiloma Acuminado/virología , Femenino , Genotipo , Humanos , Naftalenosulfonatos/química , Técnicas de Amplificación de Ácido Nucleico , Papillomaviridae/clasificación , Papillomaviridae/aislamiento & purificación , Papillomaviridae/patogenicidadRESUMEN
Hyperthermia increases expression of the antiviral cellular factors APOBEC3A and APOBEC3G and induces G-to-A or C-to-T mutations in human papilloma virus cervical cell lines and genital warts. This unexpected effect of heat treatment correlated with regression of genital warts in a subset of patients, including at distant sites, suggesting that this effect may be mediated in part by antiviral as well as immunological mechanisms.
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Condiloma Acuminado/virología , Citidina Desaminasa/genética , Hipertermia Inducida/métodos , Papillomaviridae/genética , Proteínas/genética , Condiloma Acuminado/genética , Condiloma Acuminado/terapia , Femenino , Regulación Viral de la Expresión Génica , Humanos , Mutación , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/terapia , Resultado del Tratamiento , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/virologíaRESUMEN
Apolipoprotein B mRNA-editing catalytic polypeptide (APOBEC) 3 proteins have been identified as potent viral DNA mutators and have broad antiviral activity. In this study, we demonstrated that apolipoprotein B mRNA-editing catalytic polypeptide 3A (A3A) and A3G expression levels were significantly upregulated in human papillomavirus (HPV)-infected cell lines and tissues. Heat treatment resulted in elevated expression of A3A and A3G in a temperature-dependent manner in HPV-infected cells. Correspondingly, HPV-infected cells heat-treated at 44 °C showed accumulated G-to-A or C-to-T mutation in HPV E2 gene. Knockdown of A3A or A3G could promote cell viability, along with the lower frequency of A/T in HPV E2 gene. In addition, regressing genital viral warts also harbored high G-to-A or C-to-T mutation in HPV E2 gene. Taken together, we demonstrate that apolipoprotein B mRNA-editing catalytic polypeptide 3 expression and editing function was heat sensitive to a certain degree, partly explaining the mechanism of action of local hyperthermia to treat viral warts.
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Condiloma Acuminado/terapia , Condiloma Acuminado/virología , Citidina Desaminasa/genética , Hipotermia Inducida/métodos , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/terapia , Proteínas/genética , Células Cultivadas , Condiloma Acuminado/genética , Análisis Mutacional de ADN , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Papillomaviridae/genética , Infecciones por Papillomavirus/patología , ARN Mensajero/genética , Sensibilidad y Especificidad , Regulación hacia ArribaRESUMEN
The objective of this study was to explore the expressions and significance of NDRG1 (N-myc downregulated gene family 1), VEGF (vascular endothelial growth factor) and Ki-67 in lesions of Condyloma Acuminatum (CA). Immunohistochemistry was adopted to measure the expressions of NDRG1, VEGF and Ki-67 in 48 cases of CA and 18 normal skin controls. The positive rates of NDRG1, VEGF and Ki-67 were 63. 83.33% (40/48), 93.75% (45/48) and 85.42% (41/48) in the CA tissues, and 27.78% (5/18), 94.44%(17/18) and 61.11% (11/18) in the controls, respectively. The intensities of the expressions of NDRG1, VEGF and Ki-67 in CA tissues were significantly higher than those in the controls. There were significant differences both in the positive rates and the expression intensities of NDRG1, VEGF and Ki-67 between the two groups (P less than0.05). The Spearmans Rank-Order Correlation analysis indicated that the expressions of NDRG1 protein and VEGF protein were positively correlated by the Spearmans Rank-Order Correlation analysis (r = 0.346, P=0.016). For the CA tissues with high expressions of NDRG1 and VEGF, NDRG1 and VEGF influenced both the occurrence and development of CA.
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Proteínas de Ciclo Celular/biosíntesis , Condiloma Acuminado/metabolismo , Enfermedades de los Genitales Femeninos/metabolismo , Enfermedades de los Genitales Masculinos/metabolismo , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Antígeno Ki-67/biosíntesis , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Adolescente , Adulto , Proteínas de Ciclo Celular/genética , División Celular , Condiloma Acuminado/genética , Condiloma Acuminado/patología , Femenino , Regulación de la Expresión Génica , Enfermedades de los Genitales Femeninos/genética , Enfermedades de los Genitales Femeninos/patología , Enfermedades de los Genitales Masculinos/genética , Enfermedades de los Genitales Masculinos/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Antígeno Ki-67/genética , Masculino , Persona de Mediana Edad , Factor A de Crecimiento Endotelial Vascular/genética , Adulto JovenRESUMEN
BACKGROUND: Anogenital warts are often presumed to represent nondysplastic or low-grade anal intraepithelial neoplasia (LGAIN). We previously demonstrated that up to 20% of intra-anal warts in HIV-positive men who have sex with men (MSM) contain regions of high-grade AIN (HGAIN). OBJECTIVES: To determine the causative human papillomavirus (HPV) types of low- and high- grade dysplastic areas in warts from HIV-positive MSM. METHODS: A total of 42 intra-anal warts from 41 HIV-positive MSM were graded as nondysplastic, LGAIN or HGAIN. Whole-tissue sections (WTS) were analysed with the SPF10 polymerase chain reaction/LiPA25 HPV genotyping system. If the WTS contained multiple HPV types, dysplastic regions were isolated by laser capture microdissection (LCM) for HPV genotyping. RESULTS: Overall, 38 of 42 (91%) WTS tested positive for HPV DNA. Of these, 23 (61%) contained a single HPV type and 15 (39%) contained multiple HPV types. All LCM-selected regions contained no more than one HPV type. Ten of 42 (24%) WTS contained HGAIN disease, of which six (60%) were associated with a high-risk HPV (hrHPV) genotype. Twenty-three of 42 WTS contained LGAIN disease, of which two (9%) were associated with hrHPV. AIN lesions containing hrHPV types were identified using p16 staining. CONCLUSIONS: LGAIN lesions can be caused by high-risk HPV genotypes and vice versa. We therefore recommend routine follow-up and treatment of all dysplastic intra-anal warts for HIV-positive MSM.
Asunto(s)
Neoplasias del Ano/genética , Carcinoma in Situ/genética , Condiloma Acuminado/genética , Seropositividad para VIH/genética , Homosexualidad Masculina/genética , Infecciones por Papillomavirus/genética , Adulto , Neoplasias del Ano/virología , Carcinoma in Situ/virología , ADN Viral/aislamiento & purificación , Genotipo , Seropositividad para VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Factores de RiesgoRESUMEN
OBJECTIVE: To explore the correlation of the gene polymorphisms of Toll-like receptor 2 ( TLR2) and TLR4 with the susceptibility and recurrence of condyloma acuminatum (CA). METHODS: Using Snapshot, we detected the gene polymorphisms of TLR2 597(T/C), 1350(T/C), 15607(A/G), and 2258(G/A) and TLR4 896(A/G) and 1196(C/T) in the peripheral blood of 140 CA patients and 105 HPV-negative controls. We made comparisons between the CA patients and controls as well as between the cases of recurrent CA and those of non-recurrence at 6 months after treatment. RESULTS: There were 72, 48, and 20 cases of genotype TT, TC, and CC of TLR2 597 (T/C), respectively, in the CA patients, as compared with 71, 31, and 3 cases in the controls. The gene frequency of mutant C was 31. 43% in the patients, significantly higher than 17.62% in the controls (χ2 = 12.04, P < 0.01), and it was 38.68% in the recurrent cases, remarkably higher than 27.01% in the non-recurrent cases (χ2 = 4.16, P < 0.05). There were 74, 49, and 17 cases of genotype TT, TC, and CC of TLR2 1350( T/C), respectively, in the CA patients, as compared with 73, 29, and 3 cases in the controls. The gene frequency of mutant C was 29. 64% in the patients, significantly higher than 16. 67% in the controls (χ2 =11.05, P < 0.01), and it was 36.79% in the recurrent cases, markedly higher than 25. 29% in the non-recurrent cases (χ2 = 4.18, P < 0.05). There were 44, 66, and 30 cases of genotype AA, AG, and GG of TLR2 15607(A/G), respectively, in the CA patients, as compared with 26, 58, and 21 cases in the controls. There was no significant difference in the gene frequencies of mutant G between the two groups (χ2 = 0.33, P > 0.05). No mutant genes of TLR2 2508 (G/A) or TLR4 896(A/G) and 1196(C/ T) were detected in either the CA patients or the controls. Linkage disequilibrium analysis showed a tight linkage between TLR2 597 (T/C) and 1350(T/C) (D' = 1, r2 = 0.93). CONCLUSION: TLR2 597(T/C) is tightly linked to 1350(T/C), which is correlated with both the susceptibility and the recurrence of condyloma acuminatum.
Asunto(s)
Condiloma Acuminado/genética , Frecuencia de los Genes , Polimorfismo Genético , Receptor Toll-Like 2/genética , Receptor Toll-Like 4/genética , Anciano , Estudios de Casos y Controles , Ligamiento Genético , Predisposición Genética a la Enfermedad , Genotipo , Humanos , RecurrenciaRESUMEN
BACKGROUND: Low-risk human papillomavirus (LR-HPV) infection is the main cause of genital warts. LR- HPV genotypes 6 and 11 are associated with genital warts, but there have only been a few published studies about the genotype-specific prevalence of HPV in genital warts in China. The objective of our study was to assess the prevalence of HPV genotypes for clinical cases involving both men and women and to evaluate the potential benefit of a quadrivalent (genotypes 6, 11, 16, and 18) HPV vaccine in eastern Guangdong province of China. MATERIALS AND METHODS: A total of 696 eligible patients with genital warts were enrolled during the period Aug 2009 through Oct 2014. Specimens were collected from genital warts, the HPV GenoArray test was used for HPV detection and genotyping, which could detect 21 HPV genotypes, including genotypes 6, 11, 16, and 18. RESULTS: Among the 696 cases, 675 samples were successfully genotyped. The median age of patients was 32.1 years (range, 16-67 years). The most prevalent genotypes were HPV-6 (285/675, 42.2%), HPV-11 (265/675, 39.3%), HPV-52 (52/675, 7.7%), HPV-16 (51/675, 7.56%), HPV-81 (50/675, 7.40%) and HPV-58 (37/675, 5.48%). Low-risk genotypes predominated, with a prevalence of 96.59%. The cumulative prevalence of genotypes 6 and 11 was 78.7% (531/675), the cumulative prevalence of genotypes 16 and 18 was 11.6% (78/675), and the cumulative prevalence of genotypes 6, 11, 16, and 18 was 82.5% (557/675). CONCLUSIONS: Our results provide strong evidence that, in eastern Guangdong, different from Western countries, the most prevalent low risk HPV genotypes in patients with genital warts are 6, 11 and 81. The quadrivalent HPV vaccine could prevent 82.5% of genital warts in eastern Guangdong.