INTERAÇÃO DA VIA DE SINALIZAÇÃO ROBO/SLIT NA CO-INFECÇÃO COM HPV EM TUMORES PENIANOS E SUA CORRELAÇÃO COM A CARCINOGÊNESE

Detalhes bibliográficos
Autor(a) principal: SANTOS, Maria de Lourdes Figueiredo dos
Data de Publicação: 2022
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFMA
Texto Completo: https://tedebc.ufma.br/jspui/handle/tede/tede/4269
Resumo: Introduction: Penile cancer (CP) is a rare malignancy in developed countries occurring most frequently in men aged over 60. Among other risk factors, infection with human papillomavirus (HPV) should be highlighted. Recently, efforts have been undertaken to understand which signaling pathways are deregulated in CP. Among signaling pathways involved in cell differentiation and cancer there is the one mediated by the transmembrane Roundabout (ROBO) receptor and its cognate ligands, the SLIT proteins, suggested to correlate with tumor aggressiveness in multiple types of cancer. Objective: to analyze the expression of SLIT/ROBO genes in CP and their association with HPV DNA status and clinico-pathological variables. Methods: The study adopted a transversal, quantitative approach with 75 CP samples and matched adjacent tissue samples from the Maranhão Tumor and DNA Biobank (BTMA). Sociodemographic, clinical and pathological data were retrieved from medical records. Histological subtypes were determined on hematoxylin and eosin-stained slides. Genomic DNA was isolated and used for nested PCR for HPV DNA detection. HPV types wwre determined using the Anyplex II kit. Total RNA was isolated, converted into complementary DNA (cDNA) and the expression levels of SLIT2, SLIT3, ROBO1, ROBO2 and ROBO4 were studied using real-time quantitative PCR. Results: A majority of patients (52%) earned les than the minimum wage, had incomplete fundamental education (30,59%) self-identified as married (43,53%), and lived in inner Maranhão state locations (61,76%). The condylomatous (50%) and usual (25%) histological subtypes were most prevalent. All patients presented with squamous cell carcinoma, mostly on T2 and T3 stages. 61,84% were positive for HPV DNA and HPV types 11 and 16 were most frequently identified. 60% of patients showed infections with multiple HPV types. The presence of HPV were positively correlated with daily hygiene practice and absence of lymphovascular invasion. CP samples and matched adjacent samples showed identical expression levels of all genes. HPV DNA status was not associated with differential gene expression among tumor samples. There was a significant association between reduced SLIT2 expression levels and the presence of perineural invasion (p = 0,028) as well as between higher ROBO4 levels and the presence of lymphovascular invasion (p = 0,0303). Conclusion: CP remains strongly associated with HPV infection and it is necessary to clarify the role of "low-risk" viral types such as HPV11. The SLIT/ROBO pathway does not seem to be significantly modified by penile carcinogenesis, either via HPV-related or HPV-independent pathways. SLIT2 and ROBO4 expression levels were correlated with the tumor's biological behavior, suggesting their potential use as prognostic biomarkers.
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spelling OLIVEIRA, Rui Miguel Gil da Costahttp://lattes.cnpq.br/6785759461393904BRITO, Haissa Oliveirahttp://lattes.cnpq.br/2303050934162020OLIVEIRA, Rui Miguel Gil da Costahttp://lattes.cnpq.br/6785759461393904BRITO, Haissa Oliveirahttp://lattes.cnpq.br/2303050934162020NORONHA, Elda Pereirahttp://lattes.cnpq.br/9711847705518162CABRAL, Flávia Castello Branco Vidalhttp://lattes.cnpq.br/0085459127860829CARTAGENES, Maria do Socorro Sousahttp://lattes.cnpq.br/3013333572719007http://lattes.cnpq.br/9673174973267500SANTOS, Maria de Lourdes Figueiredo dos2022-11-03T17:29:45Z2022-06-03SANTOS, Maria de Lourdes Figueiredo dos. Interação da via de sinalização Robo/Slit na Co-infecção com HPV em tumores penianos e sua correlação com a carcinogênese. 2022. 120 f. Dissertação( Programa de Pós-graduação em Saúde do Adulto) - Universidade Federal do Maranhão, São Luís, 2022.https://tedebc.ufma.br/jspui/handle/tede/tede/4269Introduction: Penile cancer (CP) is a rare malignancy in developed countries occurring most frequently in men aged over 60. Among other risk factors, infection with human papillomavirus (HPV) should be highlighted. Recently, efforts have been undertaken to understand which signaling pathways are deregulated in CP. Among signaling pathways involved in cell differentiation and cancer there is the one mediated by the transmembrane Roundabout (ROBO) receptor and its cognate ligands, the SLIT proteins, suggested to correlate with tumor aggressiveness in multiple types of cancer. Objective: to analyze the expression of SLIT/ROBO genes in CP and their association with HPV DNA status and clinico-pathological variables. Methods: The study adopted a transversal, quantitative approach with 75 CP samples and matched adjacent tissue samples from the Maranhão Tumor and DNA Biobank (BTMA). Sociodemographic, clinical and pathological data were retrieved from medical records. Histological subtypes were determined on hematoxylin and eosin-stained slides. Genomic DNA was isolated and used for nested PCR for HPV DNA detection. HPV types wwre determined using the Anyplex II kit. Total RNA was isolated, converted into complementary DNA (cDNA) and the expression levels of SLIT2, SLIT3, ROBO1, ROBO2 and ROBO4 were studied using real-time quantitative PCR. Results: A majority of patients (52%) earned les than the minimum wage, had incomplete fundamental education (30,59%) self-identified as married (43,53%), and lived in inner Maranhão state locations (61,76%). The condylomatous (50%) and usual (25%) histological subtypes were most prevalent. All patients presented with squamous cell carcinoma, mostly on T2 and T3 stages. 61,84% were positive for HPV DNA and HPV types 11 and 16 were most frequently identified. 60% of patients showed infections with multiple HPV types. The presence of HPV were positively correlated with daily hygiene practice and absence of lymphovascular invasion. CP samples and matched adjacent samples showed identical expression levels of all genes. HPV DNA status was not associated with differential gene expression among tumor samples. There was a significant association between reduced SLIT2 expression levels and the presence of perineural invasion (p = 0,028) as well as between higher ROBO4 levels and the presence of lymphovascular invasion (p = 0,0303). Conclusion: CP remains strongly associated with HPV infection and it is necessary to clarify the role of "low-risk" viral types such as HPV11. The SLIT/ROBO pathway does not seem to be significantly modified by penile carcinogenesis, either via HPV-related or HPV-independent pathways. SLIT2 and ROBO4 expression levels were correlated with the tumor's biological behavior, suggesting their potential use as prognostic biomarkers.Introdução: O câncer de pênis (CP) é uma neoplasia rara em países desenvolvidos, que acomete, sobretudo, homens a partir da sexta década de vida. Dentre os diversos fatores para o aparecimento do CP, podemos destacar a presença do papilomavírus humano (HPV, do inglês human papillomavirus). Nos últimos anos, tem-se procurado compreender quais as vias de sinalização celular desreguladas no CP. Dentre as vias relacionadas com a diferenciação celular e o câncer, podemos destacar o sistema das glicoproteínas antagonista ligante (SLIT) e do seu receptor transmembrana, Rondabout (ROBO; SLIT/ROBO), com vários estudos sugerindo que o silenciamento dessa via pode estar relacionado com a agressividade de vários tipos de tumores. Objetivo: analisar a expressão de componentes da via de sinalização SLIT/ROBO em tumores penianos e a sua associação com o HPV e variáveis clínico-patológicas. Métodos: Trata-se de um estudo quantitativo, de recorte transversal, com 75 amostras de tumores penianos e amostras de tecido adjacente, armazenadas no Banco de Tumores e DNA do Maranhão (BTMA). Os dados sociodemograficos, clínicos e patológicos foram obtidos dos prontuários dos pacientes. Os subtipos histológicos foram determinados em preparações coradas por hematoxilina e eosina. O DNA genômico das amostras foi extraído e foi realizada PCR Nested para detecção do HPV. Os tipos de HPV foram determinados usando o kit Anyplex II. O RNA das amostras foi extraído, convertido em DNA complementar (cDNA) e os níveis de expressão gênica dos genes SLIT2, SLIT3, ROBO1, ROBO2 e ROBO4 foram estudados por PCR quantitativo em tempo real. Resultados: A maioria dos pacientes ganhava menos que 1 salário mínimo (52%); a maior parcela dos pacientes tinham o ensino fundamental incompleto (30,59%); mais da metade dos pacientes referiam-se como casada (43,53%), e residia no interior do Maranhão (61,76%). O subtipo histológico que mais prevaleceu foi o condilomatoso (50%) e o usual (25%). Todos os pacientes apresentaram carcinoma escamoso, majoritariamente nos estadios T2 e T3. 61,84% foram positivos para DNA de HPV, sendo os tipos 11 e 16 mais frequentes. 60% apresentaram infecções por múltiplos tipos de HPV. A presença de HPV esteve positivamente correlacionada com a realização de higiene cotidiana e com a ausência de invasão angiolinfática. As amostras de câncer de pênis não mostraram expressão alterada de nenhum gene em comparação com as amostras adjacentes. Igualmente, a presença ou ausência de HPV não modificou a expressão de nenhum gene estudado. Foi observada uma associação entre níveis mais baixos de SLIT2 e a presença de invasão perineural (p = 0,028) e entre níveis mais elevados de ROBO4 e a presença de invasão angiolinfática (p= 0,0303). Conclusão: O CP permanece uma doença fortemente associada ao HPV, sendo necessário esclarecer o papel dos tipos de baixo risco como o HPV11. A via do SLIT/ROBO não parece ser fortemente modificada pela carcinogênese peniana relacionada com o HPV ou independente do HPV. No entanto, os níveis de expressão de SLIT2 e ROBO4 apresentam correlação com o comportamento biológico do tumor, sugerindo o seu uso como marcadores de prognóstico.Submitted by Maria Aparecida (cidazen@gmail.com) on 2022-11-03T17:29:45Z No. of bitstreams: 1 DISSERTAÇÃO Maria de Lourdes.pdf: 32062662 bytes, checksum: 5bbfc99a528c5232cae69ba8aeaf375b (MD5)Made available in DSpace on 2022-11-03T17:29:45Z (GMT). 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dc.title.por.fl_str_mv INTERAÇÃO DA VIA DE SINALIZAÇÃO ROBO/SLIT NA CO-INFECÇÃO COM HPV EM TUMORES PENIANOS E SUA CORRELAÇÃO COM A CARCINOGÊNESE
dc.title.alternative.eng.fl_str_mv Interaction of Robo/slit signaling path in co-infection with HPV in penile tumors and their correlation with carcinogenesis
title INTERAÇÃO DA VIA DE SINALIZAÇÃO ROBO/SLIT NA CO-INFECÇÃO COM HPV EM TUMORES PENIANOS E SUA CORRELAÇÃO COM A CARCINOGÊNESE
spellingShingle INTERAÇÃO DA VIA DE SINALIZAÇÃO ROBO/SLIT NA CO-INFECÇÃO COM HPV EM TUMORES PENIANOS E SUA CORRELAÇÃO COM A CARCINOGÊNESE
SANTOS, Maria de Lourdes Figueiredo dos
Câncer de Pênis;
HPV;
Via de Sinalização;
ROBO;
SLIT
Penile Cancer;
HPV;
Signaling Pathway;
ROBO;
SLIT
Cancerologia
title_short INTERAÇÃO DA VIA DE SINALIZAÇÃO ROBO/SLIT NA CO-INFECÇÃO COM HPV EM TUMORES PENIANOS E SUA CORRELAÇÃO COM A CARCINOGÊNESE
title_full INTERAÇÃO DA VIA DE SINALIZAÇÃO ROBO/SLIT NA CO-INFECÇÃO COM HPV EM TUMORES PENIANOS E SUA CORRELAÇÃO COM A CARCINOGÊNESE
title_fullStr INTERAÇÃO DA VIA DE SINALIZAÇÃO ROBO/SLIT NA CO-INFECÇÃO COM HPV EM TUMORES PENIANOS E SUA CORRELAÇÃO COM A CARCINOGÊNESE
title_full_unstemmed INTERAÇÃO DA VIA DE SINALIZAÇÃO ROBO/SLIT NA CO-INFECÇÃO COM HPV EM TUMORES PENIANOS E SUA CORRELAÇÃO COM A CARCINOGÊNESE
title_sort INTERAÇÃO DA VIA DE SINALIZAÇÃO ROBO/SLIT NA CO-INFECÇÃO COM HPV EM TUMORES PENIANOS E SUA CORRELAÇÃO COM A CARCINOGÊNESE
author SANTOS, Maria de Lourdes Figueiredo dos
author_facet SANTOS, Maria de Lourdes Figueiredo dos
author_role author
dc.contributor.advisor1.fl_str_mv OLIVEIRA, Rui Miguel Gil da Costa
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/6785759461393904
dc.contributor.advisor-co1.fl_str_mv BRITO, Haissa Oliveira
dc.contributor.advisor-co1Lattes.fl_str_mv http://lattes.cnpq.br/2303050934162020
dc.contributor.referee1.fl_str_mv OLIVEIRA, Rui Miguel Gil da Costa
dc.contributor.referee1Lattes.fl_str_mv http://lattes.cnpq.br/6785759461393904
dc.contributor.referee2.fl_str_mv BRITO, Haissa Oliveira
dc.contributor.referee2Lattes.fl_str_mv http://lattes.cnpq.br/2303050934162020
dc.contributor.referee3.fl_str_mv NORONHA, Elda Pereira
dc.contributor.referee3Lattes.fl_str_mv http://lattes.cnpq.br/9711847705518162
dc.contributor.referee4.fl_str_mv CABRAL, Flávia Castello Branco Vidal
dc.contributor.referee4Lattes.fl_str_mv http://lattes.cnpq.br/0085459127860829
dc.contributor.referee5.fl_str_mv CARTAGENES, Maria do Socorro Sousa
dc.contributor.referee5Lattes.fl_str_mv http://lattes.cnpq.br/3013333572719007
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/9673174973267500
dc.contributor.author.fl_str_mv SANTOS, Maria de Lourdes Figueiredo dos
contributor_str_mv OLIVEIRA, Rui Miguel Gil da Costa
BRITO, Haissa Oliveira
OLIVEIRA, Rui Miguel Gil da Costa
BRITO, Haissa Oliveira
NORONHA, Elda Pereira
CABRAL, Flávia Castello Branco Vidal
CARTAGENES, Maria do Socorro Sousa
dc.subject.por.fl_str_mv Câncer de Pênis;
HPV;
Via de Sinalização;
ROBO;
SLIT
topic Câncer de Pênis;
HPV;
Via de Sinalização;
ROBO;
SLIT
Penile Cancer;
HPV;
Signaling Pathway;
ROBO;
SLIT
Cancerologia
dc.subject.eng.fl_str_mv Penile Cancer;
HPV;
Signaling Pathway;
ROBO;
SLIT
dc.subject.cnpq.fl_str_mv Cancerologia
description Introduction: Penile cancer (CP) is a rare malignancy in developed countries occurring most frequently in men aged over 60. Among other risk factors, infection with human papillomavirus (HPV) should be highlighted. Recently, efforts have been undertaken to understand which signaling pathways are deregulated in CP. Among signaling pathways involved in cell differentiation and cancer there is the one mediated by the transmembrane Roundabout (ROBO) receptor and its cognate ligands, the SLIT proteins, suggested to correlate with tumor aggressiveness in multiple types of cancer. Objective: to analyze the expression of SLIT/ROBO genes in CP and their association with HPV DNA status and clinico-pathological variables. Methods: The study adopted a transversal, quantitative approach with 75 CP samples and matched adjacent tissue samples from the Maranhão Tumor and DNA Biobank (BTMA). Sociodemographic, clinical and pathological data were retrieved from medical records. Histological subtypes were determined on hematoxylin and eosin-stained slides. Genomic DNA was isolated and used for nested PCR for HPV DNA detection. HPV types wwre determined using the Anyplex II kit. Total RNA was isolated, converted into complementary DNA (cDNA) and the expression levels of SLIT2, SLIT3, ROBO1, ROBO2 and ROBO4 were studied using real-time quantitative PCR. Results: A majority of patients (52%) earned les than the minimum wage, had incomplete fundamental education (30,59%) self-identified as married (43,53%), and lived in inner Maranhão state locations (61,76%). The condylomatous (50%) and usual (25%) histological subtypes were most prevalent. All patients presented with squamous cell carcinoma, mostly on T2 and T3 stages. 61,84% were positive for HPV DNA and HPV types 11 and 16 were most frequently identified. 60% of patients showed infections with multiple HPV types. The presence of HPV were positively correlated with daily hygiene practice and absence of lymphovascular invasion. CP samples and matched adjacent samples showed identical expression levels of all genes. HPV DNA status was not associated with differential gene expression among tumor samples. There was a significant association between reduced SLIT2 expression levels and the presence of perineural invasion (p = 0,028) as well as between higher ROBO4 levels and the presence of lymphovascular invasion (p = 0,0303). Conclusion: CP remains strongly associated with HPV infection and it is necessary to clarify the role of "low-risk" viral types such as HPV11. The SLIT/ROBO pathway does not seem to be significantly modified by penile carcinogenesis, either via HPV-related or HPV-independent pathways. SLIT2 and ROBO4 expression levels were correlated with the tumor's biological behavior, suggesting their potential use as prognostic biomarkers.
publishDate 2022
dc.date.accessioned.fl_str_mv 2022-11-03T17:29:45Z
dc.date.issued.fl_str_mv 2022-06-03
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dc.identifier.citation.fl_str_mv SANTOS, Maria de Lourdes Figueiredo dos. Interação da via de sinalização Robo/Slit na Co-infecção com HPV em tumores penianos e sua correlação com a carcinogênese. 2022. 120 f. Dissertação( Programa de Pós-graduação em Saúde do Adulto) - Universidade Federal do Maranhão, São Luís, 2022.
dc.identifier.uri.fl_str_mv https://tedebc.ufma.br/jspui/handle/tede/tede/4269
identifier_str_mv SANTOS, Maria de Lourdes Figueiredo dos. Interação da via de sinalização Robo/Slit na Co-infecção com HPV em tumores penianos e sua correlação com a carcinogênese. 2022. 120 f. Dissertação( Programa de Pós-graduação em Saúde do Adulto) - Universidade Federal do Maranhão, São Luís, 2022.
url https://tedebc.ufma.br/jspui/handle/tede/tede/4269
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dc.publisher.department.fl_str_mv DEPARTAMENTO DE PATOLOGIA/CCBS
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