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1.
Medicine (Baltimore) ; 99(11): e19433, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32176070

RESUMEN

BACKGROUND: Number of studies have been performed to evaluate the relationship between the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) gene variant rs5742909 polymorphism and cervical cancer risk, but the sample size was small and the results were conflicting. This meta-analysis was conducted to comprehensively evaluate the overall association. METHODS: PubMed, Web of Science, Embase, China Biology Medical Literature database, China National Knowledge Infrastructure, WanFang, and Weipu databases were searched before July 31, 2018. The strength of associations was assessed using odds ratios (ORs) and 95% confidence intervals (CIs). All of the statistical analyses were conducted using Review Manager 5.3 and Stata 14.0. RESULTS: Eleven studies involved 3899 cases and 4608 controls. Overall, significant association was observed between the CTLA-4 gene variant rs5742909 polymorphism and cervical cancer (T vs C: OR = 1.40, 95% CI = 1.12-1.76; TT vs CC: OR = 2.22, 95% CI = 1.13-4.37; TT vs CT+CC: OR = 1.96, 95% CI = 1.03-3.74; TT+CT vs CC: OR = 1.47, 95% CI = 1.14-1.90). In subgroup analysis by ethnic group, a statistically significant association was observed in Asians (T vs C: OR = 1.56, 95% CI = 1.22-1.99), but not in Caucasians (T vs C: OR = 1.19, 95% CI = 0.87-1.62). The sensitivity analysis confirmed the reliability and stability of the meta-analysis. CONCLUSION: our meta-analysis supports that the CTLA-4 gene variant rs5742909 polymorphism might contribute to individual susceptibility to cervical cancer in Asians.


Asunto(s)
Grupo de Ascendencia Continental Asiática/genética , Antígeno CTLA-4/genética , Predisposición Genética a la Enfermedad/etnología , Polimorfismo de Nucleótido Simple , Neoplasias del Cuello Uterino/etnología , Neoplasias del Cuello Uterino/genética , Femenino , Humanos
2.
Anticancer Res ; 40(3): 1427-1436, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32132039

RESUMEN

BACKGROUND/AIM: Cervical cancer is one of the most common cancers worldwide and a major cause of cancer-related mortality among women. Previous studies have reported that microRNA-miR-187*, which is one of the non-coding parts of the genome producing small conserved ribonucleic acids, is associated with various cancers. In this study, we explored the function of miR-187* in cervical cancer cells. MATERIALS AND METHODS: miR-187* mimic, WWOX reporter constructs, siRNA and overexpression constructs were transfected into SiHa cells to investigate the function and regulatory mechanisms of miR-187*. RESULTS: Exogenous miR-187* was found to increase the oncogenic phenotypes of SiHa cells. The tumor suppressor gene WWOX is a novel target of miR-187* in SiHa cells. WWOX siRNA suppressed endogenous WWOX expression and increased the oncogenic phenotypes of SiHa cells. Exogenous WWOX expression was able to suppress the oncogenic phenotypes of SiHa cells and rescue cells from miR-187*-induced migration. CONCLUSION: miR-187* seems to enhance SiHa cervical cancer cell oncogenicity via suppression of the WWOX pathway.


Asunto(s)
MicroARNs/administración & dosificación , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/genética , Oxidorreductasa que Contiene Dominios WW/antagonistas & inhibidores , Línea Celular Tumoral , Regulación hacia Abajo , Femenino , Genes Supresores de Tumor , Humanos , MicroARNs/biosíntesis , MicroARNs/genética , ARN Interferente Pequeño/administración & dosificación , Transfección , Proteínas Supresoras de Tumor/biosíntesis , Proteínas Supresoras de Tumor/genética , Regulación hacia Arriba , Neoplasias del Cuello Uterino/patología , Oxidorreductasa que Contiene Dominios WW/biosíntesis , Oxidorreductasa que Contiene Dominios WW/genética
3.
DNA Cell Biol ; 39(5): 848-863, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32202912

RESUMEN

Cervical cancer remains a primary cause of female death in developing countries, but its prognosis can be greatly improved if patients are diagnosed earlier. In the present study, we screened the common differentially expressed genes (DEGs) of cervical squamous cell carcinoma (CESC) from dataset GSE7803, Gene Expression Omnibus, and The Cancer Genome Atlas databases. An integrated bioinformatics analysis was performed based on these DEGs for their enrichment in functions and pathways, interaction network, prognostic signature, and candidate molecular drugs. As a result, 164 (114 upregulated and 47 downregulated) DEGs of CESC were identified for further investigation. We then conducted the gene ontology term enrichment and Kyoto Encyclopedia of Genes and Genomes Pathway analyses to reveal the underlying functions and pathways of these DEGs. In the protein-protein interaction network, hub module and hub genes were identified. Five genes of significant prognostic value-DSG2, ITM2A, CENPM, RIBC2, and MEIS2-were identified by prognostic signature analysis and used to construct a risk linear model. Further validation and investigation suggested DSG2 might be a key gene in CESC prognosis. We then identified two candidate small molecules (trichostatin A and tanespimycin) against CESC. Further validation and exploration of these hub genes are warranted for future prospect in clinical applications.


Asunto(s)
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Biología Computacional , Progresión de la Enfermedad , Genes Relacionados con las Neoplasias/genética , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Pronóstico , Mapeo de Interacción de Proteínas , Bibliotecas de Moléculas Pequeñas/farmacología , Transcriptoma/efectos de los fármacos , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología
5.
DNA Cell Biol ; 39(4): 645-653, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32045269

RESUMEN

Cervical cancer (CC) is a malignant tumor that could seriously endanger women's life and health, of which cervical squamous cell carcinoma (CESC) accounts for more than 80%. High-risk human papillomavirus (HR-HPV) infection is the primary cause of CC. The 5-year survival rate is low due to poor prognosis. We need to explore the pathogenesis of CC and seek effective biomarkers to improve prognosis. The purpose of this research is to construct an HR-HPV-related long non-coding RNA (lncRNA) signature for predicting the survival and finding the biomarkers related to CC prognosis. First, we downloaded the CESC data from The Cancer Genome Atlas (TCGA) database to find HR-HPV-related lncRNAs in CC. Then, the differentially expressed lncRNAs were analyzed by univariate and multivariate Cox regression. Six lncRNAs were found to be associated with the prognosis and can be used as independent prognostic factors. Next, based on these prognostic genes, we established a risk score model, which showed that patients with higher score had poorer prognosis and higher mortality. Moreover, the Kaplan-Meier curve of the model indicated that the model was statistically significant (p < 0.05). The survival-receiver operating characteristic curve showed that the model could also predict the survival of CC patients (the area under the curve, AUC = 0.65). More importantly, nomogram was drawn with clinical features and risk score, which verified the above conclusion, and its calibration curve and c-index index fully demonstrated that the prediction model could predict the progress of CC. We also validated the risk score model in head and neck cancer, and the results indicated that the model had obvious prognostic ability. Finally, we analyzed the correlation between clinical features and survival, and found that neoplasm cancer (p < 0.000) and risk score (p < 0.000) were independent prognostic factors for CC. In conclusion, the study established HR-HPV-related lncRNA signature, which provided a reliable prognostic tool, and was of great significance for finding the biomarkers related to HR-HPV infection in CC.


Asunto(s)
Biomarcadores de Tumor/genética , Papillomaviridae/genética , ARN Largo no Codificante/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/virología , Adulto , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Humanos , Persona de Mediana Edad , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Pronóstico , Tasa de Supervivencia
6.
Int J Gynaecol Obstet ; 149(2): 237-246, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32086940

RESUMEN

OBJECTIVE: To characterize human papillomavirus (HPV) prevalence and distribution among female university students in Maputo, Mozambique, and evaluate the determinants of HPV infection. METHODS: A cross-sectional study among 504 female university students between February and April 2017. Cervicovaginal self-collected samples were analyzed for HPV genotypes by polymerase chain reaction-restriction fragment length polymorphism and AnyplexTM II HPV28 Detection kit (Seegene® ). RESULTS: The prevalence of any HPV genotype was 28.6% (144/504). Single and multiple HPV infections were detected in 76 (15.1%) and 68 (13.5%) participants, respectively. Prevalence of high-risk HPV was significantly higher than that of low-risk HPV (P<0.001). HPV16 was the most frequent genotype, followed by HPV58, HPV66, HPV52, HPV18, HPV56, HPV61, and HPV70. The prevalence of genotypes covered by the bivalent, quadrivalent, and nonavalent vaccine was 14.3%, 15.9%, and 23.4%, respectively. Number of sexual partners over lifetime and in the past 12 months was associated with HPV infection (P<0.001 and P=0.039, respectively). CONCLUSIONS: Knowledge of HPV genotype-specific prevalence among young women is important to set up strategies for HPV vaccination. The findings suggest that introduction of the nonavalent HPV vaccine might be the way forward in the present low-resource setting. In addition, self-sampling was useful for HPV detection and genotyping.


Asunto(s)
Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/epidemiología , Adolescente , Adulto , Estudios Transversales , Femenino , Genotipo , Pruebas de ADN del Papillomavirus Humano/métodos , Pruebas de ADN del Papillomavirus Humano/estadística & datos numéricos , Humanos , Persona de Mediana Edad , Mozambique/epidemiología , Papillomaviridae/genética , Infecciones por Papillomavirus/diagnóstico , Vacunas contra Papillomavirus/genética , Reacción en Cadena de la Polimerasa , Prevalencia , Factores de Riesgo , Manejo de Especímenes/métodos , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/prevención & control , Adulto Joven
7.
Mol Genet Genomics ; 295(3): 765-773, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31901979

RESUMEN

Cervical cancer is a common gynecological malignancy with high incidence and mortality. Somatic copy number alterations (CNAs) play an important role in identifying tumor suppressor genes and oncogenes and are a useful diagnostic indicator for many cancer types. However, the genomic landscape of CNAs in cervical cancer has not yet been comprehensively characterized. In the present study, we collected 974 cervical cancer samples from different data sources. All samples were analyzed by genomic arrays to obtain high-resolution CNAs. Focal genomic regions with CNA events and potential cancer driver genes were identified by GISTIC2.0. Meanwhile, we constructed a comprehensive cervical cancer database by PHP and self-written Perl and R scripts. In total, 54 recurrent regions of amplification and deletion were detected. Frequently altered tumor suppressor genes were found in these regions, including PIK3CA, ERBB2, EP300 and FBXW7. CNA hotspots and related enriched functional categories were also identified. The incidence of chromothripsis in cervical cancer was estimated to be 6.06%, and the chromosome pulverization hotspot regions were detected. Based on the curated data, we developed CNAdbCC (http://cailab.labshare.cn/CNAdbCC/), a comprehensive database for copy number alterations in cervical cancer. We provide a user-friendly Web interface for data mining and visualization. It is the most comprehensive public database devoted exclusively to genomic alterations in cervical cancer. These results extend our molecular understanding of cervical cancer. The database will enable researchers to explore specific CNA patterns in this lethal cancer and facilitate the discovery of therapeutic candidates.


Asunto(s)
Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN , Genoma Humano , Estudio de Asociación del Genoma Completo , Genómica/métodos , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Bases de Datos Genéticas , Femenino , Humanos
8.
Zhonghua Yu Fang Yi Xue Za Zhi ; 54(1): 92-98, 2020 Jan 06.
Artículo en Chino | MEDLINE | ID: mdl-31914575

RESUMEN

Objective: To investigate the role of human papillomavirus (HPV) 16 early genes E2 and E6 and heterogeneous nuclear ribonucleoprotein (hnRNP) E2 and their interaction effects in the progression of the cervical cancer. Methods: Women with normal cervix (NC), low cervical intraepithelial neoplasia (CIN Ⅰ) and high cervical intraepithelial neoplasia (CIN Ⅱ/Ⅲ) from the cervical lesions cohort in Jiexiu County of Shanxi Province from June 2014 to September 2014, and patients with cervical squamous cell carcinoma (SCC) treated at the Second Hospital of Shanxi Medical University in the same period were enrolled in this study. There were 257 participants, about 67 NC cases (26.07%), 69 CIN Ⅰ cases (26.85%), 68 CIN Ⅱ/Ⅲ cases (26.46%), and 53 SCC cases (20.62%), respectively. The information of demographic characteristics, life health habits and cervical lesions were collected by using the structured questionnaire. Cervical exfoliated cells and cervical biopsy tissues were collected to detect the infection of HPV16 and the protein expression levels of hnRNP E2, HPV16 E2 and E6. According to the median-value of the protein expression levels of hnRNP E2, HPV16 E2 and E6 and E2/E6 ratio in the NC group, the study participants were divided into the high and low expression groups/ratio groups. The multivariate logistic regression model was used to analyze the correlation between HPV16 early gene E2 and E6, hnRNP E2 and cervical cancer. The interaction effect was analyzed by using the generalized multifactor dimensionality reduction (GMDR) model. Results: The ages of NC, CIN Ⅰ, CIN Ⅱ/Ⅲ and SCC groups were (47.00±9.07), (47.64±7.35), (46.37±8.67) and (51.26±8.03) years old, respectively. The multivariate logistic regression model analysis showed that the HPV16 E2 low expression, E6 high expression and E2/E6 low ratio could increase the risk of CIN Ⅱ/Ⅲ, about OR (95%CI) values 11.11 (1.63-75.56), 8.00 (1.28-50.04), and 9.75 (1.22-77.72), respectively and SCC, about OR (95%CI) values 14.22 (2.11-95.88), 10.33 (1.67-64.00), and 12.38 (1.56-97.91), respectively. The hnRNP E2 low expression could increase the risk of CIN Ⅱ/Ⅲ and SCC, about OR (95%CI) values 3.35 (1.39-8.10) and 5.53 (1.54-19.88). The result of GMDR showed that there were interaction effects of the hnRNP E2 low expression, HPV16 E2 low expression and HPV16 E6 high expression in both CIN Ⅱ/Ⅲ and SCC groups. Conclusion: The HPV16 E2 low expression, HPV16 E6 high expression and hnRNP E2 low expression could increase the risk of high-grade cervical intraepithelial neoplasia and cervical cancer, and they might have an important interaction effect in the progression of the cervical cancer.


Asunto(s)
Carcinogénesis , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Papillomavirus Humano 16/genética , Neoplasias del Cuello Uterino/virología , Adulto , Carcinogénesis/genética , Carcinogénesis/metabolismo , China , Femenino , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo
9.
DNA Cell Biol ; 39(2): 255-272, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31977248

RESUMEN

Cervical squamous cell carcinoma (CESC) is a human papillomavirus-driven tumor that the underlying molecular mechanisms are unclear. This study aimed to elucidate the key candidate genes and potential mechanism in CESC by bioinformatics analysis. A total of 132 common differentially expressed genes (DEGs) were identified based on three expression profile data sets. A multivariate Cox proportional regression model was used to develop a four-gene prognostic signature. Mechanistically, the correlationship between MMP1 and tumor-infiltrating lymphocytes was further analyzed. Furthermore, annotations were investigated by Gene Ontology (GO) and The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, potential drugs for CESC treatment were predicted by Connectivity Map. We profiled four genes (EFNA1, ANLN, MMP1, and ZWINT) with significant prognostic values for CESC. Multiple public available data sets were used for mRNA expression and prognostic characterization. Subsequently, GO and KEGG pathway analyses showed DEGs were mainly enriched in cell cycle, immunity, and metabolic-related pathway. We then conducted an integrated analysis of MMP1, and the expression of MMP1 showed significantly inverse association with the amount of CD8+ T cells, CD4+ T cells, and macrophages infiltration. Our findings suggest the four-gene signature may be associated with prognosis. We further revealed that MMP1 may be a novel biomarker for immunotherapy, and prognostic judgment of patients with cervical cancer.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 1 de la Matriz/genética , Neoplasias del Cuello Uterino/genética , Carcinoma de Células Escamosas/diagnóstico , Femenino , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes/genética , Humanos , Pronóstico , Mapas de Interacción de Proteínas/genética , Neoplasias del Cuello Uterino/diagnóstico
10.
Gynecol Oncol ; 156(1): 203-210, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31757465

RESUMEN

OBJECTIVE: Cervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. METHODS: During 2008-2018, 154 cervical cancer patients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. RESULTS: The frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild-type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). CONCLUSIONS: More than one-third of Japanese cervical cancer patients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.


Asunto(s)
Proteínas Serina-Treonina Quinasas/genética , Neoplasias del Cuello Uterino/genética , Grupo de Ascendencia Continental Asiática/genética , Análisis Mutacional de ADN , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Femenino , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Infecciones por Papillomavirus/enzimología , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Valor Predictivo de las Pruebas , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias del Cuello Uterino/enzimología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología
11.
J Clin Pathol ; 73(1): 30-34, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31315894

RESUMEN

AIMS: The purpose of the present study was to elucidate the presence of human herpesvirus 6A (HHV-6A), HHV-6B and HHV-7 in samples of the uterine cervix through detection of viral DNA. We analysed normal tissues, samples with low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). We correlated the presence of HHV-6 and HHV-7 with the finding of human papillomavirus (HPV) in mucosal samples. METHODS: Cervical samples were examined and grouped as follows: group 1 (n=29), normal cytology; group 2 (n=61), samples with LSIL; group 3 (n=35), samples with HSIL. Molecular biology examinations were performed in all samples to detect HHV-6, HHV-7 and HPV DNA and to typify HHV-6 species. RESULTS: Group 1: normal cytology and HPV (-): HHV-6: 6.8% (2/29), HHV-7: 79.3% (23/29); group 2: LSIL and HPV (-): HHV-6: 93.1% (27/29), HHV-7: 96.5% (28/29); LSIL and HPV (+): HHV-6: 0% (0/32), HHV-7: 90.6% (29/32); group 3: HSIL and HPV (-): HHV-6: 20% (2/10), HHV-7: 70% (7/10); HSIL HPV (+): HHV-6: 12% (3/25), HHV-7: 68% (17/25). HHV-6A DNA was not detected in any samples. CONCLUSIONS: (1) Both HHV-6 and HHV-7 infect the mucosal cells of the cervix with higher prevalence of HHV-7. (2) The higher prevalence of HHV-6 in LSIL HPV (-) samples compared with those with normal cytology indicates that it constitutes a possible risk factor for atypia production. (3) The presence of HHV-7 in all samples questions its role in the production of atypia. (4) The finding of HHV-6 and HHV-7 suggests that the cervical mucosa is a possible transmission pathway for these viruses.


Asunto(s)
Neoplasia Intraepitelial Cervical/diagnóstico , ADN Viral/genética , Herpesvirus Humano 6/genética , Herpesvirus Humano 7/genética , Técnicas de Diagnóstico Molecular , Infecciones por Roseolovirus/diagnóstico , Lesiones Intraepiteliales Escamosas de Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/diagnóstico , Adolescente , Adulto , Argentina , Neoplasia Intraepitelial Cervical/genética , Neoplasia Intraepitelial Cervical/virología , Femenino , Pruebas de ADN del Papillomavirus Humano , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/virología , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Infecciones por Roseolovirus/genética , Infecciones por Roseolovirus/transmisión , Infecciones por Roseolovirus/virología , Lesiones Intraepiteliales Escamosas de Cuello Uterino/genética , Lesiones Intraepiteliales Escamosas de Cuello Uterino/virología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/virología , Adulto Joven
12.
Gene ; 723: 144142, 2020 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-31589957

RESUMEN

DNA methylation is an epigenetic alteration that may lead to carcinogenesis by silencing key tumor suppressor genes. Hypermethylation of the paired box gene 1 (PAX1) promoter is important in cervical cancer development. Here, PAX1 methylation levels were compared between Uyghur and Han patients with cervical lesions. Data on PAX1 methylation in different cervical lesions were obtained from the Gene Expression Omnibus (GEO) database, whereas data on survival and PAX1 mRNA expression in invasive cervical cancer (ICC) were retrieved from the Cancer Genome Atlas (TCGA) database. MassARRAY spectrometry was used to detect methylation of 19 CpG sites in the promoter region of PAX1, whereas gene mass spectrograms were drawn by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. Human papillomavirus (HPV) 16 infection was detected by polymerase chain reaction. PAX1 methylation in high-grade squamous intraepithelial lesion (HSIL) and ICC was significantly higher than in normal tissues. PAX1 hypermethylation was associated with poor prognosis and reduced transcription. ICC-specific PAX1 promoter methylation involved distinct CpG sites in Uyghur and Han patients HPV16 infection in HSIL and ICC patient was significantly higher than in normal women (p < 0.05). Our study revealed a strong association between PAX1 methylation and the development of cervical cancer. Moreover, hypermethylation of distinct CpG sites may induce HSIL transformation into ICC in both Uyghur and Han patients. Our results suggest the existence of ethnic differences in the genetic susceptibility to cervical cancer. Finally, PAX1 methylation and HPV infection exhibited synergistic effects on cervical carcinogenesis.


Asunto(s)
Carcinoma de Células Escamosas/virología , Metilación de ADN , Papillomavirus Humano 16/patogenicidad , Factores de Transcripción Paired Box/genética , Infecciones por Papillomavirus/diagnóstico , Lesiones Intraepiteliales Escamosas de Cuello Uterino/virología , Neoplasias del Cuello Uterino/virología , Carcinoma de Células Escamosas/genética , China/etnología , ADN Viral/genética , Bases de Datos Factuales , Regulación hacia Abajo , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Papillomavirus Humano 16/genética , Humanos , Infecciones por Papillomavirus/genética , Pronóstico , Regiones Promotoras Genéticas , Lesiones Intraepiteliales Escamosas de Cuello Uterino/genética , Análisis de Supervivencia , Neoplasias del Cuello Uterino/genética
13.
Gene ; 724: 144146, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31634561

RESUMEN

miRNA mediated genetic regulation is widely involved in carcinogenesis of cervical cancer. In this study, miR-214 was confirmed to directly regulate MKK3 via imperfect base-pairing to its 3'UTR, resulting down-regulation of its expression level. Compared to normal tissues, a down-regulated level of miR-214 was observed in cervical cancer, while MKK3 was up-regulated. Next, we demonstrated that over-expression of miR-214 or knockdown of MKK3 can inhibit the growth, proliferation, invasion and migration of cervical cancer in vitro and in vivo. Moreover, the effects of miR-214 in HeLa cells were rescued by the restoration of MKK3. In conclusion, our results laid new foundations for investigating the pathogenesis and diagnosis of cervical cancer.


Asunto(s)
MAP Quinasa Quinasa 3/genética , MicroARNs/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Regiones no Traducidas 3' , Animales , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , MAP Quinasa Quinasa 3/metabolismo , Ratones Desnudos , MicroARNs/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Genes Chromosomes Cancer ; 59(2): 84-95, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31407403

RESUMEN

Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR-E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis.


Asunto(s)
Papillomaviridae/genética , Infecciones por Papillomavirus/diagnóstico , Neoplasias del Cuello Uterino/genética , Secuencia de Bases , Carcinogénesis/genética , Carcinogénesis/metabolismo , ADN Viral/análisis , Femenino , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Persona de Mediana Edad , Papillomaviridae/patogenicidad , Infecciones por Papillomavirus/genética , Reacción en Cadena de la Polimerasa , ARN Mensajero/genética , Proteínas Represoras/genética , Proteínas Supresoras de Tumor/genética , Neoplasias del Cuello Uterino/metabolismo
15.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(10): 926-931, 2019 Oct.
Artículo en Chino | MEDLINE | ID: mdl-31814569

RESUMEN

Objective To investigate the effect of acetyl coenzyme A synthase 2 (ACSS2) on the migration and invasion induced by nutrient stress (NS) in cervical cancer cells. Methods Immunohistochemistry was used to detect the expression and distribution of ACSS2 protein in 20 pairs of cervical tumors and their adjacent normal tissues. Cervical cancer HeLa cells and the normal cervical epithelial HCvEpC cells were cultured, and serum content in culture medium was reduced from 100 to 10 mL/L as NS treatment. Western blot analysis was performed to detect the expression of ACSS2, GSK-3ß, p-GSK-3ß, ß-catenin, ß-actin, E-cadherin, vimentin. Small interfering RNA (siRNA) was used to down-regulate the expression of ACSS2. Cell migration was assessed by wound healing test, and cell invasion was tested by TranswellTM assay. Results The expression level of ACSS2 in 20 cervical tumors was significantly higher as compared with the adjacent normal tissues. The levels of ACSS2 in HeLa cells could be significantly up-regulated by NS, while no marked change was seen in HCvEpC cells. The treatment of NS promoted the epithelial mesenchymal transformation (EMT) of HeLa cells, which could be effectively reversed by siRNA-ACSS2. The scratch results showed that NS increased the healing rate of HeLa cells, which could be blocked by ACSS2 silencing. Coincidently, the number of invasive cells was elevated after NS treatment, which could be partly reversed by siRNA-ACSS2. The expression of ACSS2, p-GSK-3ß and nuclear ß-catenin was up-regulated in HeLa cells treated with NS for 48 hours, while siRNA-ACSS2 down-regulated their expression. Conclusion Silencing ACSS2 expression inhibits migration and invasion of cervical cancer cells induced by NS, which is related to down-regulated Wnt/ß-catenin signaling pathway activity.


Asunto(s)
Acetato CoA Ligasa/genética , Silenciador del Gen , Neoplasias del Cuello Uterino/patología , Vía de Señalización Wnt , Movimiento Celular , Proliferación Celular , Medios de Cultivo , Transición Epitelial-Mesenquimal , Femenino , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Invasividad Neoplásica , Neoplasias del Cuello Uterino/genética
16.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(11): 1439-1444, 2019 Nov 10.
Artículo en Chino | MEDLINE | ID: mdl-31838818

RESUMEN

Objective: To understand the infection rate and genotype distribution of high risk-human papillomavirus (HR-HPV) and the detection rate of different grades of cervical lesions in Han and Mongolian women in China and provide evidence for the development of screening and vaccination strategies for the prevention and control of cervical cancer in different ethnic groups. Methods: In June 2017, a multicenter, population-based study for cervical cancer screening in low-resource settings in China was conducted in three rural areas: Xiangyuan and Yangcheng counties in Shanxi province, and Etuoke county in Inner Mongolia Autonomous Region. A total of 9 517 women aged 30-65 years were included in the study, and two cervical and vaginal secretion samples were collected from them for HPV and PCR-based HPV DNA tests. The positive samples in any of two tests were used for PCR-based HPV genotyping test by using Sansure-pioneered One-Step Fast Release technology. Women with positive results in any the HPV tests were referred for colposcopy and punch biopsy was given if cervical intraepithelial neoplasia lesion (low-grade lesion or worse) was suspected in colposcopy evaluation. Endocervical curettage was performed if women had an unsatisfactory colposcopy exam (the squamocolumnar junction was not completely visible). Pathological detection result was used as the golden standard of diagnosis. Results: HR-HPV infection rates in Han and Mongolian women were 21.83% (1 842/8 438) and 24.93% (269/1 079), respectively. There were statistical differences in HPV infection rates between the two ethnic groups (χ(2)=5.328, P=0.021). The detection rate of cervical intraepithelial neoplasia grade 1 in Mongolian women (2.83%) was higher than that in Han women (0.87%), and the difference was statistically significant (χ(2)=33.509, P<0.001). There were no significant differences in cervical intraepithelial neoplasia grade 2 or worse detection rate between the two ethnic groups [Mongolian woman: 1.04% (11/1 059), Han Woman: 0.95% (80/8 378), χ(2)=0.069, P=0.793]. Among Han and Mongolian women with cervical intraepithelial neoplasia grade 2 or worse, the three most common HR-HPV types were HPV16, HPV52 and HPV58. There was no significant difference for multiple infection rate between Han and Mongolian women (41.37% vs. 44.35%, χ(2)=0.764, P=0.382). Conclusions: The results show that HPV infection rate in Mongolian women was higher than that in Han women. Close attention should be paid to HPV16, 52 and 58 in the prevention and control of cervical cancer in Han and Mongolian women.


Asunto(s)
Grupo de Ascendencia Continental Asiática/estadística & datos numéricos , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/virología , Lesiones Precancerosas/virología , Neoplasias del Cuello Uterino/virología , Adulto , Anciano , China/epidemiología , Colposcopía , Detección Precoz del Cáncer , Femenino , Genotipo , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/aislamiento & purificación , Humanos , Tamizaje Masivo/métodos , Persona de Mediana Edad , Papillomaviridae/clasificación , Infecciones por Papillomavirus/etnología , Infecciones por Papillomavirus/genética , Reacción en Cadena de la Polimerasa , Vigilancia de la Población , Lesiones Precancerosas/etnología , Lesiones Precancerosas/genética , Embarazo , Prevalencia , Neoplasias del Cuello Uterino/etnología , Neoplasias del Cuello Uterino/genética
17.
Klin Onkol ; 32(6): 456-462, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31842565

RESUMEN

BACKGROUND: Oncological diseases have, in most cases, a multifactorial etiology, composed of a combination of external and internal environmental factors. Hereditary tumorous syndromes are mostly autosomal dominant diseases with incomplete but very high penetrance. OBSERVATION: The patient, an 18-year-old virgin female, consulted a gynecologist in June 2018 because of metrorrhagia. Magnetic resonance imaging revealed a cervical tumor with the dimensions 80 × 90 × 80 mm. Histological analysis confirmed the presence of a very rare hypercalcemic type of small-cell carcinoma of the cervix. Further investigation of the germinal exom of the patient showed pathological variations in genes PALB2 and BRCA2, presented with recommendation of detailed examination by medical genetics. CONCLUSION: Clinical experience with this type of tumor is very limited, but it still comes with some useful outcome. Small cell carcinomas of the gynecologic tract are very rare, aggressive diseases, with very poor prognosis, affecting mainly young women. Their origin is most often the ovaries, based on most clinical data, but these tumor also localize to the endometrium, cervix, vagina and vulva. It is an extremely rare type of cancer, for which clinical data is scant due to the extremely low number of reported cases. In this patient, the carcinoma had an unusual genetical mutation burden, which she inherited from her parents. In the light of these findings, we recommend that patients suspected of having a small-cell of the gynecologic tract provide a detailed family history, and that genetic testing be considered in similar cases. This work was supported by MH CR grant 16-33209A and research program of Charles University Progress Q40/06. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 10. 6. 2019 Accepted: 9. 9. 2019.


Asunto(s)
Proteína BRCA2/genética , Carcinoma de Células Pequeñas/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Hipercalcemia/genética , Neoplasias del Cuello Uterino/genética , Adolescente , Carcinoma de Células Pequeñas/diagnóstico por imagen , Carcinoma de Células Pequeñas/patología , Femenino , Humanos , Hipercalcemia/diagnóstico por imagen , Hipercalcemia/patología , Imagen por Resonancia Magnética , Mutación , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/patología
18.
Int J Mol Sci ; 21(1)2019 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-31877944

RESUMEN

HPV-DNA integration results in dysregulation of viral oncogene expression. Because viral-cellular fusion transcripts inherently lack the viral AU-rich elements of the 3'UTR, they are considered to be more stable than episome-derived transcripts. The aim of this study is to provide formal proof for this assumption by comparing the stability of viral early transcripts derived from episomal and integrated HPV16 DNA, respectively. Full-length cDNA of three fusion transcripts comprising viral and cellular sequences in sense orientation were amplified and cloned into the adeno-viral-vector pAd/CMV/V5-DEST. The most abundant HPV16 oncogene transcript E6*I-E7-E1vE4-E5 with and without 3'UTR, served as reference and control, respectively. Human primary keratinocytes were transduced using high titer virus stocks. qRT-PCR was performed to determine mRNA stability in relation to GAPDH in the presence of actinomycin-D. In four independent transduction experiments, all three viral-cellular fusion transcripts were significantly more stable compared to the episome-derived reference. Among the three viral-cellular fusion transcripts the most stable transcript was devoid of the instability core motif "AUUUA". Unexpectedly, there was no significant difference in the stability between the episome-derived transcripts either with or without 3'UTR, indicating that the AU-rich elements of the 3'UTR are not contributing to RNA stability. Instead, the three "AUUUA" motifs located in the untranslated region between the viral E4 and E5 genes may be responsible for the instability. This is the first report showing that authentic viral-cellular fusion transcripts are more stable than episome-derived transcripts. The longer half-life of the fusion transcripts may result in increased levels of viral oncoproteins and thereby drive the carcinogenic process.


Asunto(s)
Transformación Celular Viral , Queratinocitos/metabolismo , Proteínas Oncogénicas Virales/biosíntesis , Estabilidad del ARN , ARN Viral/metabolismo , Proteínas Represoras/biosíntesis , Neoplasias del Cuello Uterino/metabolismo , Adenoviridae , Fusión Celular , Femenino , Vectores Genéticos , Humanos , Queratinocitos/patología , Proteínas Oncogénicas Virales/genética , ARN Viral/genética , Proteínas Represoras/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología
19.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 609-614, 2019 Oct 30.
Artículo en Chino | MEDLINE | ID: mdl-31699190

RESUMEN

Objective To detect the methylation status of SALL3 gene promoter region in normal cervical tissues,cervical cancer tissues,and cervical cancer cell lines and thus explore the relationship between methylation status and the expression of SALL3 gene.Methods The DNA methylation statuses of SALL3 gene in normal cervical,cervical cancer tissues and cervical cancer cell lines were analyzed by methylation-specific PCR(MS-PCR).The expressions of SALL3 mRNA in cervical cancer cell lines,cervical cancer tissues,and normal cervical tissues were detected by RT-PCR.Results In cervical cancer and matched peri-carcinomatous samples,the methylation levels of SALL3 were up-regulated(CCa vs.CCap:P=0.046;CCa vs.NC P=0.039)and the protein expressions were down-regulated(CCa vs.CCap:P=0.012;CCa vs.NC P=0.000)when compared with normal cervix samples.The mRNA levels of SALL3 in HeLa and SiHa cells treated with 5-Azacytidine were elevated in a dose-dependent manner(HeLa:P=0.001;SiHa:P=0.002).The methylation level of SALL3 was higher in high risk human papillomavirus(HPV)-positive cervical samples than in HPV-negative cervical samples(P=0.014),which also resulted in a descending SALL3 expression in HPV-positive samples(P=0.021).Conclusions The hypermethylation of SALL3 in promoter regions inhibits the expression of SALL3 in cervical cancer tissue samples.Infection with high-risk HPV serotypes may increase the methylation of SALL3 promoter region,silence its expression,and thus promote the development of cervical cancer.


Asunto(s)
Metilación de ADN , Proteínas de Homeodominio/genética , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Neoplasias del Cuello Uterino/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Células HeLa , Humanos , Infecciones por Papillomavirus/genética , ARN Mensajero/genética
20.
BMC Complement Altern Med ; 19(1): 312, 2019 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-31729992

RESUMEN

BACKGROUND: Cervical cancer is the second-leading cause of cancer-related mortality in females. Coix lacryma-jobi L. var. ma-yuen (Rom.Caill.) Stapf ex Hook. f. is the most widely recognized medicinal herb for its remedial effects against inflammation, endocrine system dysfunctions, warts, chapped skin, rheumatism, and neuralgia and is also a nourishing food. METHODS: To investigate the activity of Coix lacryma-jobi sprout extract (CLSE) on cell proliferation in human cervical cancer HeLa cells, we conducted a Cell Counting Kit-8 (CCK-8) assay. Flow-cytometric analysis and western blot analysis were performed to verify the effect of CLSE on the regulation of the cell cycle and apoptosis in HeLa cells. RESULTS: We observed that CLSE significantly inhibited cell proliferation. Furthermore, CLSE dose-dependently promoted cell cycle arrest at the sub-G1/ S phase in HeLa cells, as detected by bromodeoxyuridine (BrdU) staining. The cell-cycle-arrest effects of CLSE in HeLa cells were associated with downregulation of cyclin D1 and cyclin-dependent kinases (CDKs) 2, 4, and 6. Moreover, CLSE induced apoptosis, as determined by flow-cytometric analysis and nuclear DNA fragmentation with Annexin V/propidium iodide (PI) and 4'6'-diamidino-2-phenylindole (DAPI) staining. Induction of apoptosis by CLSE was involved in inhibition of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) and upregulation of the apoptotic proteins p53, cleaved poly (ADP-ribose) polymerase (PARP), cleaved caspase-3, and cleaved caspase-8. Finally, we observed that CLSE inactivated the phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) pathways. CONCLUSIONS: CLSE causes cell cycle arrest and apoptotic cell death through inactivation of the PI3K/AKT pathway in HeLa cells, suggesting it is a viable therapeutic agent for cervical cancer owing to its anticancer effects.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma/fisiopatología , Coix/química , Extractos Vegetales/farmacología , Neoplasias del Cuello Uterino/fisiopatología , Carcinoma/tratamiento farmacológico , Carcinoma/genética , Carcinoma/metabolismo , Caspasa 8/genética , Caspasa 8/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Coix/crecimiento & desarrollo , Femenino , Humanos , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo
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