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1.
Gene ; 766: 145119, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32946928

RESUMO

BACKGROUND: Cervical cancer is the fourth most commonly diagnosed cancer in women worldwide. The metastasis and invasion of this type of cancer are closely related to the tumor microenvironment. Immune cells and stromal cells dominate the tumor microenvironment in cervical cancer. Therefore, we should further investigate the complex interplay between the tumor progression with immune cells or stromal cells. METHODS: We downloaded the gene expression profiles and clinical data of 307 patients with cervical cancers based on the TCGA database. Subsequently, the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm was used to calculate the scores of stromal cells and immune cells in order to uncover differential expressed genes, and we analyzed the correlation between their scores and patient survival. Then the Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts (CIBERSORT) deconvolution algorithm was applied to quantify the fraction and infiltration of 22 types of immune cells in cervical cancer. Moreover, we also used R language packs and network tools to analyze GO term, gene enrichment pathway, and protein-protein relationship to trace down genes related to inflammation and immune regulation. RESULTS: The gene expression profiles and corresponding clinical data of 307 patients were obtained from TCGA database. The results showed that the scores were statistically significant between the high immunescore group and the low immunescore group. And the low immunescore group had shorter survival period than the high scores group (P = 0.035). Among the 22 types of immune cells, only T cells and mast cells were significantly related to the survival rate of cervical cancer patients. Moreover, PPI network analysis revealed that CCR5 and CXCL9, -10, -11/CXCR3 axis might be a new target for cervical cancer treatment. Finally, Kaplan-Meier survival curves found outnine representative genes significantly related to survival rate including BTNL8, CCR7, CD1E, CD6, CD27, CD79A, GRAP2, SP1B, LY9. CONCLUSIONS: These genes can be used as markers for the prognosis and diagnosis of cervical cancer and also might be used as treatment targets.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Transcriptoma/genética , Microambiente Tumoral/genética , Neoplasias do Colo do Útero/genética , Adulto , Biomarcadores Tumorais/genética , Gerenciamento de Dados , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Mapas de Interação de Proteínas/genética , Células Estromais/patologia , Neoplasias do Colo do Útero/patologia , Adulto Jovem
2.
Crit Rev Oncol Hematol ; 156: 103111, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33080526

RESUMO

Aberrant expression of lncRNAs has been seen as a key factor in a wide range of diseases including cancer. The role of lncRNAs in cervical cancer has not been clearly explained, and has been the subject of recent studies. In this review, we have compiled an updated list of previously reported lncRNAs and established a general profile of these transcripts in accordance with the role they play in cervical carcinogenesis. Thus, information here includes the influence of lncRNAs on cervical tumorigenic process through a disturbance of cellular activities. Additionally, we described recent discoveries about how HPV contributes to lncRNAs expression in cervical cancer and we summarized exploratory studies of strategies adopted to modulate the expression levels of lncRNAs to treat cervical neoplasia, by drawing attention to radio and chemo-resistance. Finally, this paper provides a broad overview that sets out new research directions about the role of lncRNAs in cervical cancer.


Assuntos
RNA Longo não Codificante , Neoplasias do Colo do Útero , Carcinogênese/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/genética
3.
PLoS One ; 15(9): e0238500, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976537

RESUMO

BACKGROUND: As per WHO, Cervical cancer (CaCx) is a global issue, being the fourth common cancer in women with incidence rate of 13.1 per 1 lakh women globally and accounting for 311000 deaths in the year 2018 itself globally. The molecular pathogenesis in Human papillomavirus (HPV) infected cases is inconclusive. The detection of molecular factors leading to progression of CaCx can be important in the diagnosis and management of the disease. p53 a known tumor suppressor gene having a regulative role in cell cycle has been highlighted as key factor in the prevention of cancer but its significance in CaCx cases has been variably documented. The present study therefore targeted to evaluate the significance of p53 profile in CaCx cases in ethnically distinct northeast Indian population. METHODS: Blood and Tissue samples (N = 85) of cervical cancer patients were collected and screening for HPV was performed using PCR. Thereafter the differential mRNA expression(qPCR), Immunohistochemistry, Mutation (PCR direct sequencing method) of p53 was studied. Further p53 epigenetic profiling was done by Methylation specific PCR (MS-PCR) and western blotting by using p53 acetylation specific antibodies. RESULTS: Our findings revealed that the downregulation of p53 was associated with the progression of disease and the variation in downregulation based on p53 polymorphism was observed. Further hypermethylation and deacetylation of p53 was also found to be associated with the pathogenesis of CaCx. The downregulated expression and hypermethylation of p53 in lower grade of CaCx, together established its association with the progression of CaCx from lower to severe grade. CONCLUSION: Therefore, in CaCx patients of northeast Indian population, malfunctioning of p53 is found to have significant role in cervical cancer progression.


Assuntos
Proteína Supressora de Tumor p53/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Adulto , Metilação de DNA , Feminino , Expressão Gênica/genética , Predisposição Genética para Doença , Genótipo , Papillomavirus Humano 16/genética , Humanos , Índia/epidemiologia , Pessoa de Meia-Idade , Papillomaviridae/metabolismo , Infecções por Papillomavirus/virologia , Polimorfismo Genético/genética , Transcriptoma/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Nat Genet ; 52(8): 800-810, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32747824

RESUMO

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.


Assuntos
Epigenoma/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Transcriptoma/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Adulto , Idoso , Metilação de DNA/genética , Feminino , Humanos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Uganda , Regulação para Cima/genética
5.
Life Sci ; 258: 118190, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32777299

RESUMO

AIMS: Glycolysis is an important process for cervical carcinoma development. Previous studies have indicated that stress-induced phosphoprotein 1 (STIP1) is associated with development of multiple tumors. Nevertheless, the role and mechanism of STIP1 in glycolysis of cervical carcinoma remain unclear. MAIN METHODS: The association between STIP1 and survival probability and the correlation between STIP1 expression and pyruvate kinase M2 (PKM2) as well as lactate dehydrogenase isoform A (LDHA) levels in cervical carcinoma were analyzed via The Cancer Genome Atlas (TCGA). The expression of STIP1, PKM2, LDHA, and cytochrome c (Cyt C) was measured via western blot or quantitative reverse transcription polymerase chain reaction. Cell viability and apoptosis were examined via cell counting kit 8 and flow cytometry, respectively. Glycolysis was assessed via detection of glucose consumption and lactate production. The protein involved in the Wnt/ß-catenin pathway was measured via western blot. KEY FINDINGS: STIP1 abundance was elevated in cervical carcinoma cells. High expression of STIP1 indicated poor survival probability. Knockdown of STIP1 inhibited cervical carcinoma cell viability and promoted apoptosis. STIP1 expression was positively correlated with PKM2 and LDHA levels in cervical carcinoma. Silence of STIP1 inhibited glycolysis and decreased PKM2 and LDHA expression. Down-regulation of STIP1 repressed the Wnt/ß-catenin pathway. Overexpression of ß-catenin reversed the effect of STIP1 silence on viability, apoptosis, glycolysis, and levels of PKM2 and LDHA. SIGNIFICANCE: STIP1 knockdown suppressed glycolysis in cervical carcinoma by inhibiting PKM2 and LDHA expression and activation of the Wnt/ß-catenin pathway.


Assuntos
Proteínas de Transporte/metabolismo , Regulação para Baixo/genética , Glicólise , Proteínas de Choque Térmico/metabolismo , Lactato Desidrogenase 5/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Neoplasias do Colo do Útero/genética , Via de Sinalização Wnt , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico/genética , Humanos , Modelos Biológicos , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt/genética
6.
DNA Cell Biol ; 39(10): 1767-1778, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32833542

RESUMO

N1-methyladenosine (m1A) is an important post-transcriptional modification in RNA, and plays critical roles in cellular functions. However, the relationship between m1A regulators and clinical significance of gynecological cancers remains unknown. In this study, we systematically analyzed RNA-seq and clinical data from several public database. Cell proliferation and migration assays were performed to verify the function of the m1A writer TRMT10C in cancer cells. We observed genetic alterations and dysregulated expressions of m1A regulators in gynecological cancer samples. We demonstrated that several m1A regulators could serve as prognostic biomarkers for gynecological cancer patients. The high correlations among the expression of m1A, N6-methyladenosine (m6A), and 5mC regulators were also revealed. Gene set enrichment analysis indicated that the mechanism of TRMT10C in regulating tumorigenesis was related to a variety of cancer-related pathways. Moreover, silencing TRMT10C suppressed the proliferation, colony formation, and migration of ovarian cancer and cervical cancer cells. In summary, our results highlight the importance of m1A regulators in regulating oncogenesis, and indicate that targeting specific m1A regulators might be a potential therapeutic strategy for gynecological cancers.


Assuntos
Biomarcadores Tumorais/genética , Metiltransferases/genética , Neoplasias Ovarianas/genética , Neoplasias do Colo do Útero/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Células HeLa , Humanos , Metiltransferases/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
7.
Acta Cytol ; 64(6): 547-555, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32683364

RESUMO

INTRODUCTION: Several studies have implicated the PIK3/AKT pathway in the pathophysiology of cancer progression as its activation seems to be aberrant in several forms of cancer. The purpose of the present systematic review is to evaluate the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer. METHODS: We used the Medline (1966-2020), Scopus (2004-2020), ClinicalTrials.gov (2008-2020), EMBASE (1980-2020), Cochrane Central Register of Controlled Trials (CENTRAL) (1999-2020), and Google Scholar (2004-2020) databases in our primary search along with the reference lists of electronically retrieved full-text papers. Statistical meta-analysis was performed with the RevMan 5.3 software. RESULTS: Overall, 12 articles were included in the present study that comprised 2,196 women with cervical cancer. Of those, 3 studies did not report significant differences in survival outcomes among patients with mutated versus wild-type PIK3CA tumors, 5 studies reported decreased survival outcomes, and 3 studies revealed increased survival rates. The meta-analysis revealed that patients with the mutated PIK3CA genotypes had worse overall survival compared to patients with wild-type PIK3CA (HR 2.31; 95% CI: 1.51, 3.55; 95% PI: 0.54, 9.96; data from 3 studies) and the same was observed in the case of DFS rates (HR 1.82; 95% CI: 1.47, 2.25; 95% PI: 1.29, 2.56; data from 4 studies). CONCLUSION: Current evidence concerning the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer is inconclusive, although the majority of included studies support a potential negative effect, primarily among those with squamous cell carcinoma tumors.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/mortalidade , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/métodos , Gerenciamento de Dados , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias do Colo do Útero/patologia
8.
Arch Biochem Biophys ; 690: 108480, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32681832

RESUMO

Although a potentially preventable disease, cervical cancer (CC) is the second most commonly diagnosed gynaecological cancer with at least 530,000 new cases annually, and the prognosis with CC is still poor. Studies suggest that aberrant expression of microRNA (miRNA) contributes to the progression of CC. As a group of small non-coding RNA with 18-25 nucleotides, miRNA regulate about one-third of all human genes. They function by repressing translation or inducing mRNA cleavage or degradation, including genes involved in diverse and important cellular processes, including cell cycling, proliferation, differentiation, and apoptosis. Results showed that misexpression of miRNA is closely related to the onset and progression of CC. This review will provide an overview of the function of miRNA in CC and the mechanisms involved in cervical carcinogenesis.


Assuntos
MicroRNAs/metabolismo , Neoplasias do Colo do Útero/genética , Animais , Apoptose/genética , Ciclo Celular/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Prognóstico , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/terapia
9.
Mutat Res ; 854-855: 503202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32660826

RESUMO

Cancer is a genomic disease associated with accumulation of genetic damage. Cancer-initiating events, such as chromosome breakage, loss and rearrangement, can be used as biomarkers to evaluate individual cancer risk. Cytokinesis-block micronucleus cytome (CBMN - Cyt) assay parameters in peripheral blood lymphocytes (PBL) of thirty four patients diagnosed with high-grade squamous intraepithelial lesions (HSIL) and fifteen healthy women were measured. The genomic instability of patients diagnosed with HSIL were investigated in order to compare differences between the two subgroups of HSIL (CIN 2 and CIN 3). The micronucleus (MN) frequencies in PBL, as well as the frequencies of nucleoplasmic bridges (NPB) and nuclear buds (NBUD) were higher in patients than in controls (Mann- Whitney test, p < 0.05). These results provide evidence that CBMN cytome assay in peripheral blood lymphocytes may be used to identify individuals who are at high risk of developing cervical cancer. Since the extent of DNA damage varies between CIN 2 and CIN 3, these findings support the CIN grading system.


Assuntos
Instabilidade Genômica/genética , Linfócitos/patologia , Lesões Intraepiteliais Escamosas/genética , Lesões Intraepiteliais Escamosas/patologia , Adulto , Idoso , Núcleo Celular/genética , Dano ao DNA/genética , Feminino , Humanos , Testes para Micronúcleos/métodos , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
10.
Life Sci ; 256: 118026, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32615187

RESUMO

AIM: We aimed to determine the biological processes and pathways involved in cervical carcinogenesis associated with high-risk human papillomavirus (HPV) infection. MATERIALS AND METHODS: Total RNA was extracted from three formalin-fixed paraffin-embedded (FFPE) samples each of normal cervix, HPV-infected low-grade squamous intraepithelial lesion (LSIL), high-grade SIL (HSIL) and squamous cell carcinoma (SCC). Transcriptomic profiling by microarrays was conducted followed by downstream Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. RESULTS: We examined the difference in GOs enriched for each transition stage from normal cervix to LSIL, HSIL, and SCC, and found 307 genes to be differentially expressed. In the transition from normal cervix to LSIL, the extracellular matrix (ECM) genes were significantly downregulated. The MHC class II genes were significantly upregulated in the LSIL to HSIL transition. In the final transition from HSIL to SCC, the immunoglobulin heavy locus genes were significantly upregulated and the ECM pathway was implicated. CONCLUSION: Deregulation of the immune-related genes including MHC II and immunoglobulin heavy chain genes were involved in the transitions from LSIL to HSIL and SCC, suggesting immune escape from host anti-tumour response. The extracellular matrix plays an important role during the early and late stages of cervical carcinogenesis.


Assuntos
Genes de Cadeia Pesada de Imunoglobulina/genética , Genes MHC da Classe II/genética , Infecções por Papillomavirus/complicações , Lesões Intraepiteliais Escamosas Cervicais/patologia , Neoplasias do Colo do Útero/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Regulação para Baixo , Matriz Extracelular/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Estadiamento de Neoplasias , Infecções por Papillomavirus/genética , Lesões Intraepiteliais Escamosas Cervicais/genética , Lesões Intraepiteliais Escamosas Cervicais/virologia , Transcriptoma , Regulação para Cima , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia
11.
Nucleic Acids Res ; 48(W1): W262-W267, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32484556

RESUMO

Although miRNA-seq is extensively used in many different fields, its quality control is frequently restricted to a PhredScore-based filter. Other important quality related aspects like microRNA yield, the fraction of putative degradation products (such as rRNA fragments) or the percentage of adapter-dimers are hard to assess using absolute thresholds. Here we present mirnaQC, a webserver that relies on 34 quality parameters to assist in miRNA-seq quality control. To improve their interpretability, quality attributes are ranked using a reference distribution obtained from over 36 000 publicly available miRNA-seq datasets. Accepted input formats include FASTQ and SRA accessions. The results page contains several sections that deal with putative technical artefacts related to library preparation, sequencing, contamination or yield. Different visualisations, including PCA and heatmaps, are available to help users identify underlying issues. Finally, we show the usefulness of this approach by analysing two publicly available datasets and discussing the different quality issues that can be detected using mirnaQC.


Assuntos
MicroRNAs/química , Análise de Sequência de RNA/normas , Software , Artefatos , Feminino , Humanos , MicroRNAs/metabolismo , Controle de Qualidade , Neoplasias do Colo do Útero/genética
12.
J Med Microbiol ; 69(7): 960-970, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32510304

RESUMO

Introduction. Persistent human papillomavirus (HPV) type 16 infection is the main causal agent of cervical cancer. Most HPV infections clear spontaneously within 1-2 years. Although not all infected women develop detectable HPV antibodies, about 60-70 % seroconvert and retain their antibodies at low levels.Aim. We investigated if cervical HPV16 DNA positivity was associated with HPV16 seroreactivity measured with two different antigen formulations. We assessed if associations were influenced by co-infection with other HPV types and HPV16 viral load.Methodology. We used baseline data for women participating in the Ludwig-McGill cohort, a longitudinal investigation of the natural history of HPV infection and cervical neoplasia. The study enrolled 2462 Brazilian women from 1993 to 1997 (pre-vaccination). ELISA assays were based on L1-only or L1+L2 virus-like particles (VLPs). Seroreactivity was expressed as normalized absorbance ratios. HPV genotyping and viral load were evaluated by PCR protocols. Pearson's r was used to measure correlations between interval-scaled variables. Serological accuracy in HPV16 DNA detection was assessed using receiver operating characteristic (ROC) curves. We analysed the association between HPV DNA positivity and HPV16 seroreactivity by linear regression.Results. Correlations between L1+L2 and L1-only VLPs for detection of HPV16 were poor (r=0.43 and 0.44 for dilutions 1 : 10 and 1 : 50, respectively). The protocol with the best accuracy was L1+L2 VLPs at serum dilution 1 : 10 (ROC area=0.73, 95 % CI: 0.65-0.85). HPV16 DNA positivity was correlated with HPV16 seroreactivity and was not influenced by co-infection or viral load. To a lesser degree, HPV16 seroreactivity was correlated with infection by other Alpha-9 papillomavirus species.Conclusion. HPV16 DNA positivity and HPV16 seroreactivity are strongly correlated. L1+L2 VLPs perform better than L1-only VLPs for detecting IgG antibodies to HPV16 in women infected with HPV16 or other Alpha-9 HPV species. This study advances our understanding of humoral immune responses against HPV16 by providing insights about the influence of VLP antigen composition to measure humoral immune response against naturally acquired HPV infection.


Assuntos
Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Infecções por Papillomavirus/diagnóstico , Adulto , Anticorpos Antivirais/sangue , Brasil , Capsídeo/imunologia , Proteínas do Capsídeo/genética , Colo do Útero/virologia , Estudos de Coortes , Feminino , Papillomavirus Humano 16/patogenicidade , Humanos , Complexo Antígeno L1 Leucocitário/imunologia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/imunologia , Neoplasias do Colo do Útero/etiologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Carga Viral/métodos , Vírion/imunologia
13.
J Cancer Res Clin Oncol ; 146(9): 2189-2203, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32488496

RESUMO

PURPOSE: Cervical cancer metastasis results in poor prognosis and increased mortality, which is not separated from inflammatory reactions accumulated by prostaglandin E2 (PGE2). As a specific G-protein coupled PGE2 receptor, EP3 is demonstrated as a negative prognosticator of cervical malignancy. Now, we aimed to investigate the pathological mechanism of EP3 in modulating cervical cancer carcinogenesis. METHODS: Bioinformatics analysis was used to identify PAI-1 and uPAR correlations with EP3 expression, as well as the prognosis of cervical cancer patients. In vitro analyses were carried out to investigate the role of EP3 on cervical cancer proliferation and migration. RESULTS: In vitro studies showed that sulprostone (an EP3 agonist) enhanced the proliferation and migration of cervical cancer cells, whereas silencing of EP3 inhibited their proliferation and migration. Furthermore, EP3 knockdown increased the expression of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator receptor (uPAR), and phosphorylated extracellular signal-regulated kinases 1/2 (p-ERK1/2), but decreased p53 expression. Bioinformatics analysis showed that both PAI-1 and uPAR were correlated with EP3 expression, as well as the prognosis of cervical cancer patients. The survival analysis further showed that uPAR overexpression (IRS≥2) was correlated with a lower overall survival rate of cervical cancer patients with advanced stages (FIGO III-IV). CONCLUSION: These results indicated that EP3 signaling pathway might facilitate the migration of cervical cancer cells through modulating uPAR expression. Therefore, EP3 and uPAR could represent novel therapeutic targets in the treatment of cervical cancer in advantaged stages.


Assuntos
Movimento Celular/genética , Dinoprostona/genética , Receptores de Prostaglandina E Subtipo EP3/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Transdução de Sinais/genética , Neoplasias do Colo do Útero/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Biologia Computacional/métodos , Dinoprostona/análogos & derivados , Dinoprostona/farmacologia , Feminino , Células HeLa , Humanos , Prognóstico , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia
14.
Cell Prolif ; 53(7): e12823, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32515533

RESUMO

OBJECTIVES: Over the past years, growing attention has been paid to deciphering the pivotal role of long non-coding RNAs (lncRNAs) in regulating the occurrence and development of human malignancies, cervical cancer (CC) included. Nonetheless, the regulatory role of lncRNA BBOX1 antisense RNA 1 (BBOX1-AS1) has not been explored as yet. MATERIAL AND METHODS: The expression of BBOX1-AS1 was detected by reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8), colony formation, TUNEL, Western blot, transwell and immunofluorescence assays testified the critical role of BBOX1-AS1 in CC. The relationship between RNAs (BBOX1-AS1, miR-361-3p, HOXC6 and HuR) was analysed by luciferase reporter, RNA Immunoprecipitation (RIP) and RNA pull-down assays. RESULTS: BBOX1 antisense RNA 1 antisense RNA 1 was revealed to be highly expressed in CC. Decreased expression of BBOX1-AS1 had suppressive effects on CC cell growth and migration. Molecular mechanism assays verified that BBOX1-AS1 had negative interaction with miR-361-3p in CC. Additionally, homeobox C6 (HOXC6) was validated to be a downstream target of miR-361-3p in CC. Furthermore, ELAV-like RNA-binding protein 1, also known as HuR, was uncovered to be capable of regulating the mRNA stability of HOXC6 in CC. More importantly, rescue assays delineated that knockdown of HuR after overexpressing miR-361-3p could reverse BBOX1-AS1 upregulation-mediated effect on CC progression. Similarly, the function induced by BBOX1-AS1 upregulation on CC progression could be countervailed by HOXC6 depletion. CONCLUSIONS: BBOX1 antisense RNA 1 facilitates CC progression by upregulating HOXC6 expression via miR-361-3p and HuR.


Assuntos
Proteína Semelhante a ELAV 1/genética , Proteínas de Homeodomínio/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Regulação para Cima/genética , Neoplasias do Colo do Útero/genética , gama-Butirobetaína Dioxigenase/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HeLa , Humanos , Ativação Transcricional/genética , Neoplasias do Colo do Útero/patologia
15.
PLoS One ; 15(6): e0234873, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559232

RESUMO

OBJECTIVE: Comparison of human mRNA microarray results from tumor-associated and normal cervical fibroblasts revealed significant TFPI2 downregulation in tumor-associated fibroblasts isolated from cervical cancer, indicating that TFPI2 downregulation may play an important role in the pathogenesis of the disease. In the present work, we investigated the mechanism of TFPI2 downregulation in tumor-associated fibroblasts and tumor cells. METHODS: In vitro models of monocultures and co-cultures were established with tumor cells and fibroblasts to explore the changes of TFPI-2 expression and epigenetic modifications of the TFPI2 gene. RESULTS: The TFPI2 gene was hypermethylated only in tumor cells. Reduction of TFPI-2 protein levels in tumor-associated fibroblasts, although the gene was not methylated, suggested alternative regulatory mechanisms of gene expression, such as inhibition by microRNAs. The expression pattern of miR-23a, a gene thought to inhibit TFPI2 translation, showed changes strongly correlated to detected TFPI-2 protein alterations. Transfections with miR-23a mimics resulted in a decrease of TFPI-2 protein expression whereas miR-23a inhibitors increased the TFPI-2 amount. Due to downregulation of miR-23a expression by HPV in cancer cells, TFPI2 was silenced by promoter methylation. In contrary, miR-23a was active in HPV-free fibroblasts and inactivated TFPI2. CONCLUSION: These results indicate dual epigenetic inhibition of TFPI2 on the transcription level by promoter methylation in cancer cells and on the translation level by miR-23a in tumor-associated fibroblasts. As a consequence, inactivation of the TFPI2 gene plays a strategic role in the progression of cervical cancer.


Assuntos
Inativação Gênica , Glicoproteínas/genética , Neoplasias do Colo do Útero/genética , Adulto , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Células Tumorais Cultivadas
16.
Life Sci ; 256: 117981, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32561395

RESUMO

Cervical cancer (CC) is regarded as the second serious threat to women's health worldwide; it's associated with certain viruses that are transmitted through sexual intercourse. Therefore, the pathogenesis of CC remains to be studied. The identified long non-coding RNAs (lncRNAs) as a key genomic product were found to be commonly dysregulated in CC and to exert significant effects in the initiation, migration, invasion and therapeutic response of CC. Therefore lncRNAs may be used as tumor suppressor genes or oncogenes to interact with DNA, RNA or proteins for the regulation of gene expression and cell signaling pathways. The relationship between single lncRNA and CC has been discovered. However, full-scale reviews on the lncRNAs function in CC are deficiency. In this review, we describe the recent reports on the dysregulated patterns regulation of lncRNAs in CC. We also conclude the recent advances on biologic functions and molecular regulation mechanism and potential clinical application of lncRNAs in CC.


Assuntos
RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células/fisiologia , Feminino , Humanos , Neoplasias do Colo do Útero/terapia
17.
PLoS One ; 15(6): e0234505, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544169

RESUMO

In order to improve treatment selection for high grade neuroendocrine carcinomas of the cervix (NECC), we performed a comparative genomic analysis between this rare tumor type and other cervical cancer types, as well as extra-cervical neuroendocrine small cell carcinomas of the lung and bladder. We performed whole exome sequencing on fresh-frozen tissue from 15 NECCs and matched normal tissue. We then identified mutations and copy number variants using standard analysis pipelines. Published mutation tables from cervical cancers and extra-cervical small cell carcinomas were used for comparative analysis. Descriptive statistical methods were used and a two-sided threshold of P < .05 was used for significance. In the NECC cohort, we detected a median of 1.7 somatic mutations per megabase (range 1.0-20.9). PIK3CA p.E545K mutations were the most frequency observed oncogenic mutation (4/15 tumors, 27%). Activating MAPK pathway mutations in KRAS (p.G12D) and GNAS (p.R201C) co-occurred in two tumors (13%). In total we identified PI3-kinase or MAPK pathway activating mutations in 67% of NECC. When compared to NECC, lung and bladder small cell carcinomas exhibited a statistically significant higher rate of coding mutations (P < .001 for lung; P = .001 for bladder). Mutation of TP53 was uncommon in NECC (13%) and was more frequent in both lung (103 of 110 tumors [94%], P < .001) and bladder (18 of 19 tumors [95%], P < .001) small cell carcinoma. These comparative genomics data suggest that NECC may be genetically more similar to common cervical cancer subtypes than to extra-cervical small cell neuroendocrine carcinomas of the lung and bladder. These results may have implications for the selection of cytotoxic and targeted therapy regimens for this rare disease.


Assuntos
Carcinoma Neuroendócrino/genética , Variações do Número de Cópias de DNA/genética , Genômica , Neoplasias do Colo do Útero/genética , Adulto , Carcinoma Neuroendócrino/patologia , Colo do Útero/metabolismo , Colo do Útero/patologia , Cromograninas/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Estudos de Coortes , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53 , Neoplasias do Colo do Útero/patologia , Sequenciamento Completo do Exoma
18.
PLoS Pathog ; 16(6): e1008624, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555725

RESUMO

Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3'UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment.


Assuntos
Transformação Celular Viral , MicroRNAs/metabolismo , Papillomaviridae/metabolismo , Infecções por Papillomavirus/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Neoplasias do Colo do Útero/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Proteínas Serina-Treonina Quinases/genética , RNA Neoplásico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
19.
J Cancer Res Clin Oncol ; 146(8): 1971-1978, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32447484

RESUMO

PURPOSE: Interleukin-10 (IL-10) is an immunoregulatory cytokine and its cervical and serum concentrations have been associated with a poor prognosis of cervical cancer. The rs1800872 polymorphism (c.-592C>A) in the promotor region of the IL-10 gene affects the production and expression of IL-10 and thus is able to determine the immune response profile in the cervix. Therefore, the aim of this work is to state the association between IL-10 c.-592C>A polymorphism and cervical cancer. METHODS: Genomic DNA was extracted from patient's peripheral blood and tumor biopsy. Socio-demographic, sexual behavior and reproductive characteristics data were collected using a questionnaire. RESULTS: Co-dominant model in logistic binary regression adjusted for confounders, showed that patients presenting with C/A genotype had 2.15 times more chances for developing cervical cancer (OR 2.15; CI95% 1.02-4.56). The dominant model, C/A + A/A, was also independently associated with 2.71 times more chances for cervical cancer development when compared to control patients (OR 2.71; CI95% 1.05-4.47). CONCLUSION: Our study analyses show the association between cervical cancer and IL-10 c.-592C>A polymorphism, demonstrating that the allele A presence was independently associated with higher risks of cervical cancer development.


Assuntos
Interleucina-10/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Estudos de Casos e Controles , DNA/sangue , DNA/genética , Feminino , Genótipo , Humanos , Interleucina-10/biossíntese , Interleucina-10/imunologia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/imunologia
20.
Yonsei Med J ; 61(5): 371-381, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32390360

RESUMO

PURPOSE: Cervical cancer is one of the most fatal diseases among women in under-developed countries. To improve cervical cancer treatment, discovery of new targets is needed. In this study, we investigated the expression of NUP210, miR-22, and Fas in cervical cancer tissues and their functions in cell cycle regulation. MATERIALS AND METHODS: We detected and compared the expression levels of NUP210, miR-22, and Fas in cervical cancer tissues with paired normal tissues using immunohistochemistry, Western blot, and real-time quantitative polymerase chain reaction. NUP210 was knocked down in HeLa cells via lentivirus, followed by cell cycle and proliferation analysis. Using a luciferase reporter assay, we explored the link between miR-22 and NUP210. We overexpressed miR-22 in HeLa cells and analyzed cell cycle and proliferation function. We then overexpressed miR-22 in NUP210 knockdown cells to explore the connection between Fas and miR-22-NUP210 signaling. RESULTS: We found that NUP210 was overexpressed in cervical cancer patients. Knocking down NUP210 restored cell apoptosis and proliferation. We confirmed miR-22 as a regulator of NUP210 and verified that miR-22 was inhibited in cervical cancer development. We also found that restoring miR-22 expression could induce cell apoptosis. Finally, we found that miR-22-regulated expression of NUP210 could alter Fas expression and, in turn, elicit cell cycle arrest and proliferation. CONCLUSION: miR-22 in cervical cancer is downregulated, resulting in NUP210 overexpression and inhibition of Fas-induced cell apoptosis.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , MicroRNAs/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Receptor fas/metabolismo , Adulto , Apoptose/genética , Carcinogênese/genética , Carcinogênese/patologia , Proliferação de Células/genética , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
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