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2.
Braz. j. med. biol. res ; 54(11): e11592, 2021. tab, graf
Article in English | LILACS | ID: biblio-1339449

ABSTRACT

Cervical cancer (CC) patients have a poor prognosis due to the high recurrence rate. However, there are still no effective molecular signatures to predict the recurrence and survival rates for CC patients. Here, we aimed to identify a novel signature based on three types of RNAs [messenger RNA (mRNAs), microRNA (miRNAs), and long non-coding RNAs (lncRNAs)]. A total of 763 differentially expressed mRNAs (DEMs), 46 lncRNAs (DELs), and 22 miRNAs (DEMis) were identified between recurrent and non-recurrent CC patients using the datasets collected from the Gene Expression Omnibus (GSE44001; training) and The Cancer Genome Atlas (RNA- and miRNA-sequencing; testing) databases. A competing endogenous RNA network was constructed based on 23 DELs, 15 DEMis, and 426 DEMs, in which 15 DELs, 13 DEMis, and 390 DEMs were significantly associated with disease-free survival (DFS). A prognostic signature, containing two DELs (CD27-AS1, LINC00683), three DEMis (hsa-miR-146b, hsa-miR-1238, hsa-miR-4648), and seven DEMs (ARMC7, ATRX, FBLN5, GHR, MYLIP, OXCT1, RAB39A), was developed after LASSO analysis. The built risk score could effectively separate the recurrence rate and DFS of patients in the high- and low-risk groups. The accuracy of this risk score model for DFS prediction was better than that of the FIGO (International Federation of Gynecology and Obstetrics) staging (the area under receiver operating characteristic curve: training, 0.954 vs 0.501; testing, 0.882 vs 0.656; and C-index: training, 0.855 vs 0.539; testing, 0.711 vs 0.508). In conclusion, the high predictive accuracy of our signature for DFS indicated its potential clinical application value for CC patients.


Subject(s)
Humans , Female , Uterine Cervical Neoplasms/genetics , MicroRNAs/genetics , RNA, Long Noncoding/genetics , RNA, Messenger , Gene Expression Regulation, Neoplastic , Disease-Free Survival , rab GTP-Binding Proteins , Ubiquitin-Protein Ligases , Neoplasm Recurrence, Local/genetics
3.
Braz. j. med. biol. res ; 54(11): e11363, 2021. graf
Article in English | LILACS | ID: biblio-1339445

ABSTRACT

Cervical cancer (CC) is the most common malignant tumor in females. Although persistent high-risk human papillomavirus (HPV) infection is a leading factor that causes CC, few women with HPV infection develop CC. Therefore, many mechanisms remain to be explored, such as aberrant expression of oncogenes and tumor suppressor genes. To identify promising prognostic factors and interpret the relevant mechanisms of CC, the RNA sequencing profile of CC was downloaded from the Cancer Genome Atlas and the Gene Expression Omnibus databases. The GSE63514 dataset was analyzed, and differentially expressed genes (DEGs) were obtained by weighted coexpression network analysis and the edgeR package in R. Fifty-three shared genes were mainly enriched in nuclear chromosome segregation and DNA replication signaling pathways. Through a protein-protein interaction network and prognosis analysis, the kinesin family member 14 (KIF14) hub gene was extracted from the set of 53 shared genes, which was overexpressed and associated with poor overall survival (OS) and disease-free survival (DFS) of CC patients. Mechanistically, gene set enrichment analysis showed that KIF14 was mainly enriched in the glycolysis/gluconeogenesis signaling pathway and DNA replication signaling pathway, especially in the cell cycle signaling pathway. RT-PCR and the Human Protein Atlas database confirmed that these genes were significantly increased in CC samples. Therefore, our findings indicated the biological function of KIF14 in cervical cancer and provided new ideas for CC diagnosis and therapies.


Subject(s)
Humans , Female , Uterine Cervical Neoplasms/genetics , Papillomavirus Infections , Gene Expression Regulation, Neoplastic , Cell Cycle/genetics , Kinesin/genetics , Oncogene Proteins , Disease-Free Survival , Computational Biology , Protein Interaction Maps
4.
Article in Chinese | WPRIM | ID: wpr-880821

ABSTRACT

OBJECTIVE@#To explore the strategy of pregnancy-preserving and maternal- fetal management in patients with primary gynecologic neuroendocrine tumors (gNETs) during pregnancy.@*METHODS@#We performed whole genome sequencing (WGS) for analyzing maternal and fetal somatic and germline single nucleotide variations (SNVs) and small insertions and deletions (InDels) for a 29-year-old pregnant woman diagnosed with stage IB2 large cell neuroendocrine carcinoma (LCNEC) and adenocarcinoma in the cervix. A systematic literature review was performed to explore the strategies for treatment of such rare histological type while maintaining pregnancy.@*RESULTS@#Global case analysis of cervical NETs during pregnancy suggested that negative lymph node metastasis and an early FIGO stage were potentially associated with a good prognosis of the patients. In the case presented herein, a pregnancy-preserving strategy was adopted and favorable maternal-fetal outcomes were achieved after neoadjuvant chemotherapy, radical surgery and postoperative systemic chemotherapy. At 35@*CONCLUSIONS@#Although gNETs in pregnancy are rare and highly risky, pregnancy-preserving managements of gNETs can still be considered and favorable maternalfetal outcomes are possible with proper assessment of the clinical indications and implementation of multimodal treatments. Precise treatment and follow-up strategies based on the results of WGS for risk-reducing intervention of cancer recurrence or occurrence can potentially benefit the patient and the neonate.


Subject(s)
Adenocarcinoma , Adult , Carcinoma, Neuroendocrine/genetics , Child , Female , Humans , Infant, Newborn , Neoplasm Recurrence, Local , Pregnancy , Uterine Cervical Neoplasms/genetics
5.
Rev. colomb. cancerol ; 24(3): 140-145, jul.-set. 2020. tab, graf
Article in Spanish | LILACS | ID: biblio-1144333

ABSTRACT

Resumen El desarrollo y la innovación de nuevas tecnologías ha permitido mejorar la detección de la infección por el virus del papiloma humano de alto riesgo. La captura de híbridos II es un ensayo que se basa en hibridación y quimioluminiscencia. Cobas VPH Test es una PCR cualitativa y Aptima VPH Assay permite detectar la expresión de ARN mensajero de las oncoproteínas E6/E7 del VPH de alto riesgo. Estas técnicas presentan ventajas en comparación con la citología convencional, que se utiliza como prueba de rutina para la detección temprana del cáncer de cuello uterino. En el estudio ESTAMPA se realizaron 13.691 procesamientos que permitieron identificar que para el planteamiento de proyectos de investigación o para la implementación de pruebas de tamizaje de VPH es necesario analizar las ventajas y desventajas de las pruebas del mercado.


Abstract The development and innovation of new technologies has improved the detection of high-risk human papillomavirus infection. Hybrid capture II is an assay that is based on hybridization and chemiluminescence. Cobas HPV Test is a qualitative PCR and Aptima HPV Assay allows to detect the expression of messenger RNA of the high- risk HPV E6 / E7 oncoproteins. These techniques have advantages, in comparison, with conventional cytology that is routinely used for the detection of cervical cancer. In the ESTAMPA study, 13,691 prosecutions were carried out that allowed to identify that for the planning of research projects or for the implementation of HPV screening tests, it is necessary to analyze the advantages and disadvantages of market tests.


Subject(s)
Humans , Female , Papillomaviridae/isolation & purification , Research Design , Uterine Cervical Neoplasms/diagnosis , Papillomavirus Infections/diagnosis , Molecular Diagnostic Techniques/methods , Papillomaviridae/genetics , DNA, Viral , RNA, Messenger , Uterine Cervical Neoplasms/genetics , Mass Screening , Multicenter Studies as Topic , Triage , Papillomavirus Infections/genetics , Human Papillomavirus DNA Tests , Luminescent Measurements , Nucleic Acid Hybridization
6.
Article in Chinese | WPRIM | ID: wpr-880799

ABSTRACT

OBJECTIVE@#To explore the inhibitory effects of silencing long non-coding RNA (LncRNA) HIF1A-AS2 on epithelialmesenchymal transition (EMT) and tumor stem cell-like phenotype in cervical cancer cells.@*METHODS@#We designed 3 shRNA constructs for silencing HIF1A-AS2 in CaSki cells, and the shRNA with the strongest interference effect was selected for subsequent experiment. CaSki cells were transfected with shRNA-NC or Sh-HIF1A-AS2, and the changes in cell viability, invasion ability, EMT, expressions of EMT-related proteins, formation of cell spheres and expressions of stem cell markers were detected.@*RESULTS@#Transfection with shRNA-NC and Sh-HIF1A-AS2 did not significantly affected the viability of CaSki cells (@*CONCLUSIONS@#Silencing HIF1A-AS2 can inhibit proliferation, invasion and migration of cervical cancer cells


Subject(s)
Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Hypoxia-Inducible Factor 1, alpha Subunit , RNA, Long Noncoding/genetics , RNA, Small Interfering/genetics , Uterine Cervical Neoplasms/genetics
7.
Biol. Res ; 52: 33, 2019. tab, graf
Article in English | LILACS | ID: biblio-1019498

ABSTRACT

BACKGROUND: Studies have shown that cancer susceptibility candidate 11 (CASC11), a newly discovered long non-coding RNA (lncRNA), was aberrantly overexpressed in hepatic carcinoma, gastric cancer and colorectal cancer. However, its effects on cervical cancer has been kept unknown up to now. The present study was aimed to investigate the relationship between lncRNA CASC11 and cervical cancer and further explore the mechanism of CASC11 effect on cervical cancer progression. MATERIALS: Quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the expressions of CASC11 in cancerous and adjacent normal tissues of patients with cervical cancer as well as in cell lines. The proliferation, migration, invasion and apoptosis were assayed after transfecting the cell with si-CASC11 or pcDNA3.1-CASC11. TOP/FOP-Flash luciferase reporter assay and western blot were used to analysis the activation of Wnt/ß-catenin signaling pathway. Si-CASC11-transfected HeLa cells were subcutaneously inoculated into male athymic (nude) mice to investigate the effect of CASC11 on the tumor formation. RESULTS: We discovered that CASC11, the expression of which was positively associated with the tumor size and the FIGO staging and negatively related to the patients' survival rate, was up-regulated in the cervical cancer tissues and cell lines. Silencing CASC11 inhibited the proliferation, migration as well as invasion and promoted the cell apoptosis. Conversely, overexpression of CASC11 facilitated the cancer cell's proliferation, migration and invasion ability and suppressed the apoptosis. Further study showed that CASC11 promoted the migration and invasion of cervical cancer cells by activating Wnt/ß-catenin signaling pathway and silencing CASC11 inhibited the tumor growth in vivo. CONCLUSION: Our study demonstrated that CASC11 promoted the cervical cancer progression by activating Wnt/ß-catenin signaling pathway for the first time, which provides a new target or a potential diagnostic biomarker of the treatment for cervical cancer.


Subject(s)
Humans , Animals , Female , Mice , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology , Genetic Predisposition to Disease , MicroRNAs/genetics , beta Catenin/genetics , Wnt Signaling Pathway/genetics , Uterine Cervical Neoplasms/virology , Apoptosis/genetics , Disease Progression , Papillomavirus Infections/complications , Cell Proliferation/genetics , Genome-Wide Association Study , Flow Cytometry
8.
Braz. j. med. biol. res ; 52(1): e7567, 2019. graf
Article in English | LILACS | ID: biblio-974265

ABSTRACT

Cervical cancer is one of the most common cancers among women around the world. However, the underlying mechanism involved in cervical cancer progression is incompletely known. In the present study, we determined the role of glycoprotein nonmetastatic melanoma protein B (GPNMB) in tumorigenesis of cervical cancer. According to the GEO database, we found that GPNMB expression was significantly higher in cervical cancer than in normal cervix epithelium. A similar pattern was observed in GPNMB expression in cultured cervical cancer cells and normal cervical epithelial cells. Compared with the control, GPNMB knockdown significantly decreased the proliferation and migration capacity, but enhanced the apoptosis capacity of SiHa and HeLa cells. Additionally, the activity of MMP-2 and MMP-9 were aberrantly increased in SiHa and HeLa cells compared with normal cervical epithelial cells, whereas their activities were strongly inhibited by GPNMB siRNA. Furthermore, Wnt/β-catenin signaling was activated by GPNMB in SiHa and HeLa cells. Increased MMP-2/MMP-9 expression was suppressed by Dkk-1, inhibitor of Wnt/β-catenin signaling, while it was enhanced by stimulator BIO. The proliferation, migration, and apoptosis capacity of HeLa cells were found to be affected by Dkk-1 and BIO to different extents. In conclusion, we demonstrated that GPNMB contributed to the tumorigenesis of cervical cancer, at least in part, by regulating MMP-2/MMP-9 activity in tumor cells via activation of canonical Wnt/β-catenin signaling. This might be a potential therapeutic target for treating human cervical cancer.


Subject(s)
Humans , Female , Membrane Glycoproteins/metabolism , Gene Expression Regulation, Neoplastic/genetics , Uterine Cervical Neoplasms/metabolism , beta Catenin/metabolism , Wnt Signaling Pathway/genetics , Membrane Glycoproteins/genetics , Cell Movement , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology , Blotting, Western , Apoptosis , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , RNA, Small Interfering/metabolism , Cell Line, Tumor , Cell Proliferation , beta Catenin/genetics
9.
Mem. Inst. Oswaldo Cruz ; 111(11): 663-669, Nov. 2016. tab
Article in English | LILACS | ID: biblio-829247

ABSTRACT

Human papillomavirus (HPV) infections are strongly associated with the development of cervical intraepithelial neoplasias and invasive cervical cancer. Polymorphisms in cytokine-encoding genes and behavioural cofactors could play an important role in protecting an individual against viral infections and cancer. Here, we investigated whether IL-6 -174 G>C, IL-8 +396 G>T, and TGF-β1 +869 G>C and +915 G>C polymorphisms were associated with susceptibility to HPV infection in women from north-east (Pernambuco) Brazil. We analysed 108 healthy uninfected women (HC) and 108 HPV-positive women with cervical lesions. Genetic polymorphisms were assessed using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism. Comparison of the distribution of the genotypic and allelic frequencies of the IL-18 +396 T>G polymorphism between HPV infected woman an uninfected controls showed that the GG genotype and G allele were both more frequent in the HC group, and were associated with protection from HPV infection (p = 0.0015; OR = 0.29 CI95% = 0.13-0.61; p = 0.0005; OR = 0.45 CI95% 0.29-0.7, respectively). Individuals from the control group could have previously had HPV infection that was spontaneously eliminated; however, it was undetectable at the time of sample collection. Based on our findings, we hypothesize that the IL-8 +396 G>T polymorphism could interfere with susceptibility to HPV infection, by modulating the ability of immune system to fight the virus.


Subject(s)
Humans , Female , Adolescent , Adult , Middle Aged , Aged , Young Adult , Cervical Intraepithelial Neoplasia/genetics , Interleukin-6/genetics , Interleukin-8/genetics , Papillomavirus Infections/genetics , Polymorphism, Single Nucleotide , Transforming Growth Factor beta1/genetics , Uterine Cervical Neoplasms/genetics , Alleles , Base Sequence , Brazil , Cervical Intraepithelial Neoplasia/virology , Cross-Sectional Studies , DNA, Viral/analysis , Gene Frequency , Genetic Predisposition to Disease , Papillomavirus Infections/virology , Polymerase Chain Reaction , Uterine Cervical Neoplasms/virology
10.
Article in English | WPRIM | ID: wpr-100610

ABSTRACT

OBJECTIVE: DNA methylation has been shown to be a potential biomarker for early cancer detection. The aim of this study was to evaluate DNA methylation profiles according to liquid-based Pap (LBP) test results and to assess their diagnostic value in a Korean population. METHODS: A total of 205 patients with various Papanicolaou test results were enrolled to this study (negative, 26; atypical squamous cells of undetermined significance, 39; low grade squamous intraepithelial lesion, 44; high grade squamous intraepithelial lesion (HSIL), 48; and cancer, 48). DNA methylation analysis of four genes, ADCYAP1, PAX1, MAL, and CADM1, was performed on residual cervical cells from LBP samples using a quantitative bisulfite pyrosequencing method. To evaluate the diagnostic performance of the four methylated genes for cancer detection, receiver operating characteristic (ROC) curves were drawn. Sensitivities and specificities were also tested at cutoffs determined from the ROC curves. RESULTS: Cervical cancer cells showed dramatically increased methylation levels for the four genes analyzed. ADCYAP1 and PAX1 also trended toward elevated methylation levels in HSIL samples, although the levels were much lower than those in cancer cells. The sensitivities of methylated ADCYAP1, PAX1, MAL, and CADM1 for the detection of cancer were 79.2%, 75.0%, 70.8%, and 52.1%, and the specificities were 92.0%, 94.0%, 94.7%, and 94.0%, respectively. Methylated ADCYAP1 and PAX1 demonstrated relatively better discriminatory ability than did methylated MAL and CADM1 (area under the curves 0.911 and 0.916 vs. 0.854 and 0.756, respectively). CONCLUSION: DNA methylation status, especially in the ADCYAP1 and PAX1 genes, showed relatively good specificity, ranging from 90% to 94%. The possible additive and complementary roles of DNA methylation testing with respect to conventional cervical cancer screening programs will need to be validated in prospective population-based studies.


Subject(s)
Alphapapillomavirus/genetics , Atypical Squamous Cells of the Cervix/pathology , Cell Adhesion Molecules/genetics , DNA Methylation , Female , Genotype , Humans , Immunoglobulins/genetics , Myelin and Lymphocyte-Associated Proteolipid Proteins/genetics , Paired Box Transcription Factors/genetics , Papanicolaou Test , Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , ROC Curve , Squamous Intraepithelial Lesions of the Cervix/genetics , Uterine Cervical Neoplasms/genetics , Vaginal Smears
11.
Article in English | IMSEAR | ID: sea-162077

ABSTRACT

Introduction: Human papillomavirus (HPV) is a DNA virus which has tropism for epithelial cells, is the major etiological factor for development of cervical precancerous and cancerous lesions. Nearly 100 diff erent types of HPV have been characterized and thereare a large number of other types. HPV infection is one of the most common causes of sexually transmitted disease in both men and women worldwide. It is associated with a variety of clinical conditions that range from innocuous lesions to cancer. Genital HPV types are divided into high and low-risk types, according to the oncogenic potential. Molecular and epidemiologic studies have solidifi ed the association between high risk HPV types (especially HPV-16 and HPV-18) and cervical squamous cell carcinoma. HPV infection is often transient and self-limiting but infection may persists and progress to high grade lesions and cancer. In addition to persistent high-risk HPV infection, other viral factors such as high viral loads, HPV variants, infections with multiple high-risk HPV types and genetic predisposition contribute to the development of cervical cancer. Th e aim of the present study was to detect HPV DNA and identify high risk HPV genotype among women having cervical intraepithelial neoplasia and carcinoma and to evaluate potential effi cacy of prophylactic HPV vaccine. Methods: Cervical swab from histopathologically diagnosed CIN (n=51) and carcinoma (n=39) patients were taken and high risk HPV DNA was detected by HC II assay. Polymerase Chain Reaction was used to identify high risk HPV genotype. Result: HPV DNA was detected in 41 (45.56%) patients by HC II assay. HPV type 16 was detected in 27 (81.82%) followed by type 18 in 3 (9.09%) and type 45 in 2 (6.06%) cases of cervical carcinoma. Among precancerous cases, only type 16 was detected. Conclusion: Knowledge based on HPV prevalence and genotype could be used to predict the effi cacy of cost eff ective prophylactic vaccine, introduction of newer generation vaccine and management of cervical carcinoma.


Subject(s)
Adult , DNA, Viral/genetics , Female , Genotype/genetics , Genotyping Techniques/methods , Human Papillomavirus DNA Tests/methods , Humans , Human Papillomavirus DNA Tests/methods , Papillomaviridae/genetics , Precancerous Conditions/epidemiology , Precancerous Conditions/genetics , Risk , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/genetics , Young Adult , Uterine Cervical Neoplasms/therapy
12.
Rev. bras. ginecol. obstet ; 36(5): 205-210, 05/2014. tab, graf
Article in English | LILACS | ID: lil-712755

ABSTRACT

PURPOSE: To investigate protein expression and mutations in phosphatase and tensin homolog (PTEN) in patients with stage IB cervical squamous cell carcinoma (CSCC) and the association with clinical-pathologic features, tumor p53 expression, cell proliferation and angiogenesis. METHODS: Women with stage IB CSCC (n=20 - Study Group) and uterine myoma (n=20 - Control Group), aged 49.1±1.7 years (mean±standard deviation, range 27-78 years), were prospectively evaluated. Patients with cervical cancer were submitted to Piver-Rutledge class III radical hysterectomy and pelvic lymphadenectomy and patients in the Control Group underwent vaginal hysterectomy. Tissue samples from the procedures were stained with hematoxylin and eosin for histological evaluation. Protein expression was detected by immunohistochemistry. Staining for PTEN, p53, Ki-67 and CD31 was evaluated. The intensity of PTEN immunostaining was estimated by computer-assisted image analysis, based on previously reported protocols. Data were analyzed using the Student's t-test to evaluate significant differences between the groups. Level of significance was set at p<0.05. RESULTS: The PTEN expression intensity was lower in the CSCC group than in the Control (benign cervix) samples (150.5±5.2 versus 204.2±2.6; p<0.001). Our study did not identify any mutations after sequencing all nine PTEN exons. PTEN expression was not associated with tumor expression of p53 (p=0.9), CD31 (p=0.8) or Ki-67 (p=0.3) or clinical-pathologic features in patients with invasive carcinoma of the cervix. CONCLUSIONS: Our findings demonstrate that the PTEN protein expression is significantly diminished in CSCC. .


OBJETIVO: O objetivo do estudo foi investigar a expressão e mutações do PTEN em pacientes com Carcinoma de Células Escamosas (CCE) de Colo do Útero com estadiamento IB e sua associação com fatores prognósticos, expressão do p53, proliferação celular e angiogênese. MÉTODOS: Mulheres com diagnóstico de CCE de colo uterino em estágio IB (n=20) (casos) e mioma uterino (n=20) (controle) com idade de 49.1±1.7 foram acompanhadas. As pacientes com câncer de colo do útero foram submetidas a histerectomia Piver-Rutledge classe III associada a linfadenectomia pélvica e aquelas com mioma uterino a histerectomia vaginal. Amostras de tumor e colo normal foram retiradas para avaliação histológica e marcação imuno-histoquímica das proteínas PTEN, p53, ki-67 e CD 3. A intensidade imuno-histoquímica do PTEN foi estimada por processamento de imagem digital a partir de protocolos pré-estabelecidos. Os dados foram analisados através do teste de qui - quadrado (χ2). O nível de significância foi considerado quando p < 0,05. RESULTADOS: A expressão do PTEN estava diminuída no grupo de pacientes com CCE em comparação ao grupo controle (150.5±5.2 versus 204.2±2.6; p<0.001). Nenhuma mutação no seqüenciamento genético dos nove exons do PTEN foi encontrada. Não houve associação estatisticamente significativa entre a expressão do PTEN e a expressão do p53 (p=0,969), Ki-67 (p=0.283) e CD 31 (p=0.817) ou fatores prognósticos anátomo-clínicos nas pacientes com carcinoma invasor do colo uterino. CONCLUSÕES: Este estudo demonstrou que o PTEN estava significativamente diminuído nas pacientes com CCE. .


Subject(s)
Adult , Aged , Female , Humans , Middle Aged , /biosynthesis , Carcinoma, Squamous Cell/genetics , PTEN Phosphohydrolase/biosynthesis , PTEN Phosphohydrolase/genetics , Uterine Cervical Neoplasms/genetics , Gene Expression Regulation, Neoplastic , /biosynthesis , Mutation , Prospective Studies , /biosynthesis , Uterine Cervical Neoplasms/pathology
13.
Biol. Res ; 47: 1-7, 2014. graf, tab
Article in English | LILACS | ID: biblio-950757

ABSTRACT

BACKGROUND: Telomeres are protective caps consisted of specific tandem repeats (5'-TTAGGG-3'). Shortening of telomeres at each cell division is known as "mitotic clock" of the cells, which renders telomeres as important regulators of lifespan. TRF2 is one of the critical members of shelterin complex, which is a protein complex responsible from the preservation of cap structure, and loss or mutation of TRF2 results in DNA damage, senescence or apoptosis. Since cancer is frequently associated with aberrant cell cycle progression, defective DNA repair or apoptosis pathways, TRF2 could be one likely candidate for cancer therapy. Here we investigated the prognostic role of TRF2 levels in cervical cancer patients. Fold-induction rates were evaluated with respect to median values after real-time PCR analysis. Overall survival, distant disease-free and local recurrence-free survival rates were calculated using Kaplan-Meier long rank test. RESULTS: Both five year overall- and disease-free survival rates were longer in patients with higher TRF2 expression compared to lower expression, but results were not statistically significant (69.2% vs 28.9%, respectively). Mean local recurrence-free survivals (LRF) were very close ( 58.6, CI: 44.3-72.9 vs 54.5, CI: 32.1-76.9 months) for high and low expressions, respectively. Cumulative proportion of LRF at the end of five year period was 76.9% for high and 57.1% for low TRF2 expression (P = 0.75). Statistically significant difference was found between survival ratios and Bcl-xL and p53 gene expressions, but not with TRF2. A respectable correlation between TRF2 expression and apoptosis along with distant metastasis was noted (P = 0.045 and 0.036, respectively). Additionally, high TRF2 expression levels had a positive impact in five year survival rate of stage IIIB-IVA patients (P = 0.04). CONCLUSIONS: Our results support the role of TRF2 in apoptosis and imply a positive relation with distant metastases and survival in advanced stage patients. The remarkable difference in survival periods of patients with different TRF2 expressions suggest that TRF2 may be a candidate factor to estimate survival for cervical cancer, a preliminary observation which should further be verified with a larger cohort.


Subject(s)
Humans , Female , Adult , Middle Aged , Aged , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/mortality , Telomere/metabolism , Telomeric Repeat Binding Protein 2/metabolism , Recurrence , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology , Survival Rate , Tumor Suppressor Protein p53/analysis , Apoptosis/genetics , Statistics, Nonparametric , Disease-Free Survival , In Situ Nick-End Labeling , bcl-X Protein/analysis , Kaplan-Meier Estimate , Real-Time Polymerase Chain Reaction , Neoplasm Staging
14.
Femina ; 41(2)março - abril. tab
Article in Portuguese | LILACS | ID: lil-694482

ABSTRACT

A infecção pelo Papilomavírus humano (HPV) é o principal responsável pela ocorrência do câncer cervical, sendo que o seu estudo por meio de técnicas moleculares sofreu um aumento significativo na última década. Objetivo: Analisar as publicações sobre a identificação molecular do HPV no colo uterino no Brasil. Metodologia:Trata-se de revisão sistemática nos portais PubMed e Biblioteca Virtual em Saúde entre os anos de 2007 a 2012, utilizando os termos: “human papillomavirus”, “cervical cancer”, “polymerase chain reaction” e “Brazil”. Dos 37 artigos identificados, 16 permaneceram após leitura dos mesmos na integra, sendo excluídos: os disponíveis apenas o resumo; os estudos que focaram a população masculina; os retrospectivos; com dados dos tipos de HPV indisponíveis; estudos experimentais; comparativo de técnicas; e de variantes intratípicas. De posse desses artigos, realizou-se a distribuição entre a frequência dos tipos de HPV em relação às diferentes técnicas de genotipagem e regiões do Brasil onde ocorreram as pesquisas que originaram os artigos. Resultados: Houve um predomínio das publicações na região Sudeste (43,7%), seguido pelo Nordeste (25,0%) e Sul (18,7%). Dos 16 artigos incluídos, observou-se uma maior frequência pelo HPV tipo 16 seguido do 31. Conclusão:As técnicas de diagnóstico moleculares são importantes ferramentas para a identificação dos tipos de HPV presentes em infecções do colo uterino, observando a necessidade de identificação dos genótipos que predominam na população brasileira, com a finalidade de melhoria na elaboração de políticas públicas em saúde.


he infection by human papillomavirus (HPV) is the main responsible for the occurrence of cervical cancer, and their study using molecular techniques has increased significantly in the last decade. Objective: To analyze the publications on the molecular identification of HPV in cervical cancer in Brazil. Methodology: This is a systematic review in PubMed and Virtual Health Library postals between the years 2007 and 2012 using the terms: “humanpapillomavirus”, “cervical cancer”, “polymerasechainreaction” and “Brazil.” Out of the 37 articles identified, 16 remained after their fully reading, being excluded: available only the summary, the studies that focused on the male population; retrospective; with data of HPV types unavailable; experimental studies, comparative techniques; and intratypical variants. Based on these articles the frequency distribution of HPV types was held relative to different genotyping techniques and regions of Brazil where the articles research took place. Results: There was a predominance of publications in the Southeast (43.7%), followed by the Northeast (25.0%) and South (18.7%) out of the 16 articles included, we observed a higher frequency of HPtion of HPV types in cervical infections, observing the need for identification of genotypes that predominate in the Brazilian population, with the aim of improving the development of public health policies.


Subject(s)
Humans , Female , Uterine Cervical Neoplasms/etiology , Uterine Cervical Neoplasms/genetics , Papillomaviridae/genetics , Molecular Diagnostic Techniques , Brazil , In Situ Hybridization/methods , Papillomavirus Infections/genetics , Papillomavirus Infections/transmission , /genetics , /isolation & purification , /genetics , /isolation & purification , Polymerase Chain Reaction/methods , Genotyping Techniques/methods
15.
Medicina (B.Aires) ; 72(6): 461-466, dic. 2012. tab
Article in English | LILACS | ID: lil-662152

ABSTRACT

The mortality rate for cervical cancer (CC) in Northern Argentina is three times higher than the average for the country (7.8 deaths/100 000 women). We determined the prevalence and genotype distribution of human papillomavirus (HPV) in 227 sexually active women of the native Pilagá community in Formosa, Argentina. We also conducted an HPV-16 variant analysis and studied several community factors that might play a role in viral entry and infection. Endo- and exocervical samples were tested for HPV DNA with MY09/11-PCR or with GP5+/6+-PCR. HPV was detected in 46.7% of the samples and 21 different types were found; the most frequent being HPV-16 (19.4%), -6 and -18 (5.3%), -58 (3.5%) and -31 and -33 (3.1%). In relation to HPV-16 variants, 68.2% were European and 31.8% Asian-American. Among the cofactors analyzed only disposal of human excreta to the open air (P=0.01) was significantly associated with HPV infection. Our prevalence estimates clearly show that Pilagá women are highly exposed to or infected with high risk HPV types and therefore are at a high risk of developing precancerous lesions and eventually CC at the population level.


La tasa de mortalidad por cáncer cervical (CC) en la región norte de la Argentina es tres veces más alta que la media del país (7.8 muertes/100 000 mujeres). En el presente trabajo se determinó la prevalencia de infección por virus papiloma humano (VPH) y la distribución y frecuencia de los genotipos en 227 mujeres sexualmente activas de la etnia aborigen Pilagá (Formosa, Argentina). También se realizó un análisis de las variantes intratípicas de VPH-16 presentes en la comunidad y se analizaron diversos factores socioculturales que podrían tener algún rol destacado en la transmisión de la infección viral. Se estudiaron muestras de células endo-exocervicales mediante PCR basadas en los cebadores MY09/11 y GP5+/6+ con posterior restricción enzimática y/o hibridación dot-blot. La infección por VPH fue detectada en el 46.7% de las mujeres analizadas. Fueron identificados 21 genotipos, de los cuales los más frecuentes fueron HPV-16 (19.4%), -6 y -18 (5.3%), -58 (3.5%) y -31 y -33 (3.1%). Respecto al HPV-16, se encontraron 68.2% de variantes europeas y 31.8% de asiático-americanas. Entre los cofactores analizados, solo la disposición de excretas al aire libre estuvo significativamente asociada con la infección por VPH (P = 0.01). Los datos obtenidos reflejan que la comunidad Pilagá está altamente expuesta a las infecciones por genotipos de alto riesgo de VPH, lo cual puede estar asociado a una alta incidencia de lesiones cervicales preneoplásicas y neoplásicas.


Subject(s)
Adolescent , Adult , Aged , Female , Humans , Middle Aged , Young Adult , Cervix Uteri/virology , DNA, Viral/isolation & purification , Papillomaviridae/genetics , Papillomavirus Infections/epidemiology , Precancerous Conditions/virology , Uterine Cervical Neoplasms/genetics , Argentina/epidemiology , Argentina/ethnology , Genotype , Papanicolaou Test , Prevalence , Papillomavirus Infections/genetics , Population Groups/ethnology , Precancerous Conditions/pathology , Risk Factors , Socioeconomic Factors , Uterine Cervical Neoplasms/prevention & control
16.
Femina ; 40(5)set.-out. 2012.
Article in Portuguese | LILACS | ID: lil-668402

ABSTRACT

O câncer de colo uterino é uma importante causa de morte entre as mulheres em países subdesenvolvidos. A infecção persistente pelo papilomavírus humano (HPV) oncogênico e o comprometimento da resposta imune são fatores de risco para o desenvolvimento da neoplasia intraepitelial cervical (NIC) e sua progressão para o câncer cervical invasivo. O diagnóstico precoce e o tratamento das lesões precursoras do câncer são de grande importância. Estudos epigenéticos estão sendo realizados com o objetivo de avaliar sua influencia nos processos de oncogênese, visto que alterações epigenéticas estão presentes em quase todos os tumores. A metilação de DNA e a acetilação de histonas são as duas mudanças epigenéticas mais estudadas. O melhor entendimento do perfil epigenético na neoplasia intraepitelial cervical e no câncer cervical invasor pode ser utilizado no diagnóstico e prognóstico deste câncer. O objetivo desta revisão consistiu em entender as mudanças epigenéticas encontradas até o momento nas pacientes com NIC e câncer de colo uterino. Foi realizada revisão da literatura de estudos indexados em banco de dados, como PubMed e LILACS. Verificou-se que, até o presente momento, não há um marcador de metilação que tenha o desempenho adequado para servir como indicador para as lesões precursoras do câncer, ou mesmo para o carcinoma cervical.


The cervical cancer is a major cause of death among women in developing countries. Persistent infection by human papillomavirus (HPV) and oncogenic involvement of the immune response are risk factors for the development of cervical intraepithelial neoplasia (CIN) and its progression to invasive cervical cancer. Early diagnosis and treatment of cancer precursor lesions are of great importance. Epigenetic studies are being conducted to evaluate its influence in the process of oncogenesis, since epigenetic alterations are present in almost all tumors. DNA methylation and histone acetylation are the two most studied epigenetic changes. An improved understanding of the epigenetic profile in CIN and invasive cervical cancer can be used in the diagnosis and prognosis of this cancer. The aim of this review was to understand the epigenetic changes found to date in patients with CIN and cervical cancer. We performed a literature review of studies indexed in databases such as PubMed and LILACS. It was found that, to our knowledge, there is no methylation marker with an adequate performance to serve as an indicator for cancer precursor lesions, or even for cervical carcinoma.


Subject(s)
Humans , Female , DNA Methylation , Cervical Intraepithelial Neoplasia/etiology , Cervical Intraepithelial Neoplasia/genetics , Early Detection of Cancer , Epigenesis, Genetic , Histones/genetics , Papillomavirus Infections/immunology , Precancerous Conditions/prevention & control , Uterine Cervical Neoplasms/genetics , Prognosis
17.
Braz. j. microbiol ; 43(2): 744-753, Apr.-June 2012. ilus, graf, tab
Article in English | LILACS | ID: lil-644492

ABSTRACT

Infection with high risk Human papillomavirus (HR-HPV) is necessary but not sufficient to cause cervical carcinoma. This study explored whether multiple HR-HPV or coinfection with Epstein-Barr virus (EBV) influence the integration status of HPV16 genome. The presence and typing of HPV in a series of 125 cervical specimens were assessed by polymerase chain reaction (PCR) using the specific primers for the HPV L1 region. As for EBV infection, the viral EBNA1 gene was used for its detection through PCR amplification. Disruption of the HPV E2 gene was assessed by amplification of the entire E2 gene with single set of primers, while E2 transcripts were evaluated by a reverse transcription PCR method (RT-PCR). The overall prevalence of HPVDNA was of 81.8% in cervical cancers versus 26.9% in benign lesions. In HPV positive cases, HPV16 and HPV18 were the most prevalent types, followed by HPV types 33, 31. EBV EBNA1 prevalence was statistically more frequent in cervical carcinomas than in benign lesions (29.5%, vs 9.6%; P=0.01). No viral infection was detected in healthy control women. The uninterrupted E2 gene was correlated with the presence of E2 transcripts originating from the HPV episomal forms. It was observed that integration was more common in HPV18 and EBV coinfection. The presence of EBV caused a five-fold [OR= 5; CI= 1.15-21.8; P = 0.04] increase in the risk of HPV16 genome integration in the host genome. This study indicates that EBV infection is acting as a cofactor for induction of cervical cancer by favoring HPVDNA integration.


Subject(s)
Humans , Gene Amplification , Genome , Herpesviridae Infections , /genetics , Uterine Cervical Neoplasms/genetics , Papillomavirus Infections , /genetics , Risk Factors , Reverse Transcriptase Polymerase Chain Reaction/methods , Polymerase Chain Reaction/methods , Electrophoresis , Methods , Patients , Prevalence
18.
Braz. j. microbiol ; 43(1): 389-392, Jan.-Mar. 2012.
Article in English | LILACS | ID: lil-622829

ABSTRACT

This study aimed to evaluate the use of the FTA elute cardTM impregnated with cervicovaginal sample directly in the PCR amplification for detection of HPV-DNA. The results were compared to a reference technique. This method was more efficient than the protocol indicated by the manufacturer, identifying 91.7% against 54.2% of the positive samples.


Subject(s)
Humans , Female , Chancre/genetics , Chancre/pathology , In Vitro Techniques , Uterine Cervical Neoplasms/genetics , Polymerase Chain Reaction/methods , Determination , Incidence , Methods , Outpatients , Protocols , Methods
19.
Indian J Pathol Microbiol ; 2011 Oct-Dec 54(4): 695-699
Article in English | IMSEAR | ID: sea-142094

ABSTRACT

Objective: The purpose of the present study was to determine the differential expression pattern of cyclooxygenase-2 (COX-2) in patients of carcinoma of uterine cervix and its correlation with tumor differentiation and lymphovascular invasion. Materials and Methods: Seventy (70) cases of cervical carcinoma were included (20 in-situ, 42 invasive squamous cell, and 8 cases of adenocarcinoma). Formalin-fixed paraffin-embedded tissue sections were stained by Hematoxylin and Eosin. Immunohistochemistry for COX-2 were performed on these blocks. Results: A higher expression of COX-2 was seen in invasive squamous cell carcinoma than in in-situ carcinoma (P = 0.002). Five out of eight cases of adenocarcinoma showed strong positivity for COX-2 antibody. Among the histopathological correlates, tumor differentiation did not show a positive correlation (P = 0.717), while lymphovascular invasion was associated with positive staining in majority of the cases (P = 0.001). Conclusion: Expression of COX-2 is more in cases of invasive than in in-situ carcinoma. Adenocarcinomas showed a strong expression of COX-2. A positive association of COX-2 expression and the presence of lymphovascular emboli were found in the present study. COX-2 inhibitors need to be studied as a therapeutic adjunct for the treatment of carcinoma cervix.


Subject(s)
Adult , Carcinoma/genetics , Carcinoma/pathology , Cervix Uteri/pathology , Cyclooxygenase 2/genetics , Female , Gene Expression Profiling , Histocytochemistry , Humans , Immunohistochemistry , Microscopy , Middle Aged , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology
20.
GJO-Gulf Journal of Oncology [The]. 2011; July (10): 18-26
in English | IMEMR | ID: emr-146109

ABSTRACT

Cervical cancer is the second most common cancer in women worldwide after breast cancer. Cervical cancer is a preventable disease. The implementation of cervical cancer screening programs has greatly decreased the morbidity and mortality, as precancerous lesions and early invasive cervical cancer could be detected and treated effectively. The detection of hTERC gene amplification was suggested as a possible diagnostic marker for use in routine cytological screening. The present study was designed to detect genomic gains of the hTERC and C-MYC genes using FISH technique and to investigate the relationship between genes amplification and the clinical data of the patients. The current study was carried out on twelve cases with cervical cancer at different grades [three cases were grade I, six cases were grade II and three cases were grade III]. Interphase FISH analysis using LSI probe, Cervical Cancer probe hTERC [3q26] and C-MYC [8q24], was successfully performed on 12 patients with cancer cervix. Interphase FISH analysis revealed positive hTERC gene amplification in all cases of cancer cervix [100%]. However C-MYC gene amplification was detected in four cases only [33.3%]. Statistical analysis of the data revealed significant correlation between hTERC amplification and grating. Also, there was significant correlation between C-MYC amplification and grading and highly significant correlation between C-MYC amplification and hTERC amplification. On the other hand hTERC and C-MYC genes amplification showed an inverse correlation with the ages of the patients. The present study highlights the importance of using hTERC and C-MYC genes FISH probes for cases with cancer cervix or pre-malignant lesions as a sensitive technique. This method provides an easy and effective applicable approach which helps in the diagnosis and prognosis, as an increased copy number is associated with a more advanced grade that could be detected in the early stages of the disease


Subject(s)
Humans , Female , Genes, myc , Chromosome Banding , In Situ Hybridization, Fluorescence , Neoplasm Grading , Telomerase/genetics , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology
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