Made available in DSpace on 2014-10-09T12:32:40Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:09:11Z (GMT). No. of bitstreams: 1 03364.pdf: 2751554 bytes, checksum: 360960c959ad71d04aabe33771c4ef04 (MD5) / Dissertacao (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN/CNEN-SP

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Orientador: Silvia Regina Rogatto / Banca: Maria Inês de Moura Campos Pardini / Banca: Carlos Eduardo Bacchi / Resumo: O câncer de mama (CM) ocupa o primeiro lugar em incidência e o segundo em mortalidade entre as mulheres no mundo. É considerada uma doença heterogênea com alterações em diversas vias de sinalização molecular. Os fatores prognósticos atuais são incapazes de predizer a evolução da totalidade dos pacientes, assim como os marcadores preditivos não conseguem evitar que grande parte das pacientes com CM sejam submetidas à tratamento desnecessário. A busca de outros marcadores tumorais, tanto prognósticos quanto preditivos tem sido alvo de inúmeras pesquisas, que buscam predizer a evolução clínica de um número maior de pacientes. Dois marcadores tumorais com possíveis implicações clínicas são o TGFB1 e o seu receptor TGFBR2. No entanto, o papel do TGFB1 na carcinogênese e na progressão do câncer de mama ainda não é totalmente conhecido. Desta forma, o objetivo deste estudo foi avaliar a expressão do TGFB1 e do TGFBR2 em tumores de mama e correlacionar com os dados clínicos e histopatológicos. Para tanto, foram analisadas 49 amostras de carcinomas ductais invasivos primários e sete amostras de mamas normais como controles pelas técnicas de RT-PCR quantitativa em tempo real (qRTPCR) e imunohistoquímica (IHQ). Os resultados mostraram que baixos níveis de expressão protéica de TGFB1 nas células tumorais estavam associados a menor sobrevida livre de doença. Os tumores apresentaram acentuada diminuição da expressão do transcrito TGFBR2 quando comparados ao controle normal. Além disso, foram observados baixos níveis dos transcritos TGFB1 e TGFBR2 nos tumores com fenótipos mais agressivos (alto índice proliferativo e estadio avançado). Esses dados sugerem que o TGFB1 atua como supressor tumoral em CMs e que a diminuição da expressão TGFB1 e TGFBR2 é um evento importante na carcinogênese mamária. A detecção dos níveis de expressão protéica... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Breast cancer (BC) is the leading female cancer in incidence and the second one in mortality worldwide. BC is considered a heterogeneous disease, that presents abnormalities in several molecular pathways. The known prognostic markers are not capable to predict the outcome of all the patients, as well as the predictive markers are not capable to avoid unnecessary treatments. It is necessary to search for other tumor markers, even prognostic and predictive, regarding the prediction of a higher number of patient's outcome. Two tumor markers with possible clinical implications are TGFB1 and its receptor TGFBR2. However the role of TGFB1 in carcinogenesis and in the BC progression is not totally understood yet. In this way, the aim of this study was to analyze the expression of TGFB1 and TGFBR2 in breast tumors and to correlate it with clinical and histopathological data. For this, it were analyzed 49 ductal invasive carcinomas and 7 normal breast tissues as controls with quantitative real time PCR (qRT-PCR) and immunohistochemistry (IHC) technologies. The results showed that low expression levels of TGFB1 protein in tumor cells were associated with a lower disease-free survival. Tumors presented highly diminished TGFBR2 transcript expression when compared with normal controls. Moreover, low levels of TGFB1 and TGFBR2 transcripts were observed in tumors with aggressive phenotypes (high proliferation index and advanced stage). These results suggests that TGFB1 acts like a tumor supressor in BCs and that the TGFB1 and TGFBR2 lowering expression is an important event in mammary carcinogenesis. The detection of tumor TGFB1 protein expression levels can be helpful in clinical practice like a prognostic marker in mammary carcinomas. / Mestre

Made available in DSpace on 2014-06-11T19:33:24Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-08-27Bitstream added on 2014-06-13T20:05:14Z : No. of bitstreams: 1 nascimentoepontes_mg_dr_botfm.pdf: 553102 bytes, checksum: 6f4ebc00fc0583f012e1a99ab95ffefe (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Toxicam / Urinary bladder carcinomas (UBC) frequently recur. During the intervals “free‐ofneoplasia”, between the initially diagnosed tumor and its recurrences, there are not undisputable histological alterations in the mucosa, although some studies have reported DNA damage in urothelial cells. In order to understand developmental characteristics of UBC, primary tumors and their recurrences were cytogenetically evaluated for their genomic expression by High Resolution Comparative Genomic Hybridization (HR‐CGH). Tumors and their respective recurrences, six low‐grade (LG) and five high‐grade (HG) cases, provided 20 tissue samples that were submitted to laser microdissection capture followed by HR‐CGH. HR‐CGH profiles had two different analyses – all tumors altogether or classified according to their respective histological grades. Both comparisons showed high frequency (80%) of gains in 11p12 and losses in 16p12, in agreement with the literature that indicate alterations of 11p and 16p in UBC recurrences. These findings suggest that those chromosome regions contain putative oncogenes and tumor suppressor genes critical for urinary bladder carcinogenesis. Within a same patient genomic profile showed high agreement between tumors and their respective recurrences, i.e., tumors from the same patient showed a large number of common losses and gains. The high similarities of genomic alterations in successive tumors from the same patient suggest that a stable genomic profile was established in UBCs and their recurrences. Besides, during the “free‐of‐neoplasia” intervals, negative urinary bladder washes were submitted to Fluorescent in situ Hybridization (FISH) to detect quantitative alterations in centromeres 7 (n=21 samples), 17 (n= 21) and 9p21 (n=36). No numerical alterations... (Complete abstract click electronic access below)

Made available in DSpace on 2014-06-11T19:27:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-28Bitstream added on 2014-06-13T18:56:52Z : No. of bitstreams: 1 paiva_ce_me_botfm.pdf: 1255697 bytes, checksum: 3b134e3a9a4224016105b510cbe1c230 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / O câncer de mama (CM) ocupa o primeiro lugar em incidência e o segundo em mortalidade entre as mulheres no mundo. É considerada uma doença heterogênea com alterações em diversas vias de sinalização molecular. Os fatores prognósticos atuais são incapazes de predizer a evolução da totalidade dos pacientes, assim como os marcadores preditivos não conseguem evitar que grande parte das pacientes com CM sejam submetidas à tratamento desnecessário. A busca de outros marcadores tumorais, tanto prognósticos quanto preditivos tem sido alvo de inúmeras pesquisas, que buscam predizer a evolução clínica de um número maior de pacientes. Dois marcadores tumorais com possíveis implicações clínicas são o TGFB1 e o seu receptor TGFBR2. No entanto, o papel do TGFB1 na carcinogênese e na progressão do câncer de mama ainda não é totalmente conhecido. Desta forma, o objetivo deste estudo foi avaliar a expressão do TGFB1 e do TGFBR2 em tumores de mama e correlacionar com os dados clínicos e histopatológicos. Para tanto, foram analisadas 49 amostras de carcinomas ductais invasivos primários e sete amostras de mamas normais como controles pelas técnicas de RT-PCR quantitativa em tempo real (qRTPCR) e imunohistoquímica (IHQ). Os resultados mostraram que baixos níveis de expressão protéica de TGFB1 nas células tumorais estavam associados a menor sobrevida livre de doença. Os tumores apresentaram acentuada diminuição da expressão do transcrito TGFBR2 quando comparados ao controle normal. Além disso, foram observados baixos níveis dos transcritos TGFB1 e TGFBR2 nos tumores com fenótipos mais agressivos (alto índice proliferativo e estadio avançado). Esses dados sugerem que o TGFB1 atua como supressor tumoral em CMs e que a diminuição da expressão TGFB1 e TGFBR2 é um evento importante na carcinogênese mamária. A detecção dos níveis de expressão protéica... / Breast cancer (BC) is the leading female cancer in incidence and the second one in mortality worldwide. BC is considered a heterogeneous disease, that presents abnormalities in several molecular pathways. The known prognostic markers are not capable to predict the outcome of all the patients, as well as the predictive markers are not capable to avoid unnecessary treatments. It is necessary to search for other tumor markers, even prognostic and predictive, regarding the prediction of a higher number of patient’s outcome. Two tumor markers with possible clinical implications are TGFB1 and its receptor TGFBR2. However the role of TGFB1 in carcinogenesis and in the BC progression is not totally understood yet. In this way, the aim of this study was to analyze the expression of TGFB1 and TGFBR2 in breast tumors and to correlate it with clinical and histopathological data. For this, it were analyzed 49 ductal invasive carcinomas and 7 normal breast tissues as controls with quantitative real time PCR (qRT-PCR) and immunohistochemistry (IHC) technologies. The results showed that low expression levels of TGFB1 protein in tumor cells were associated with a lower disease-free survival. Tumors presented highly diminished TGFBR2 transcript expression when compared with normal controls. Moreover, low levels of TGFB1 and TGFBR2 transcripts were observed in tumors with aggressive phenotypes (high proliferation index and advanced stage). These results suggests that TGFB1 acts like a tumor supressor in BCs and that the TGFB1 and TGFBR2 lowering expression is an important event in mammary carcinogenesis. The detection of tumor TGFB1 protein expression levels can be helpful in clinical practice like a prognostic marker in mammary carcinomas.

Orientador: João Lauro Viana de Camargo / Coorientador: Silvia Regina Rogatto / Banca: Claudia Aparecida Rainho / Banca: Mônica Vannucci Nunes Lipay / Banca: Carlos Márcio Nóbrega de Jesus / Banca: Leopoldo Alves Ribeiro Filho / Resumo: Não disponível / Abstract: Urinary bladder carcinomas (UBC) frequently recur. During the intervals "free‐ofneoplasia", between the initially diagnosed tumor and its recurrences, there are not undisputable histological alterations in the mucosa, although some studies have reported DNA damage in urothelial cells. In order to understand developmental characteristics of UBC, primary tumors and their recurrences were cytogenetically evaluated for their genomic expression by High Resolution Comparative Genomic Hybridization (HR‐CGH). Tumors and their respective recurrences, six low‐grade (LG) and five high‐grade (HG) cases, provided 20 tissue samples that were submitted to laser microdissection capture followed by HR‐CGH. HR‐CGH profiles had two different analyses - all tumors altogether or classified according to their respective histological grades. Both comparisons showed high frequency (80%) of gains in 11p12 and losses in 16p12, in agreement with the literature that indicate alterations of 11p and 16p in UBC recurrences. These findings suggest that those chromosome regions contain putative oncogenes and tumor suppressor genes critical for urinary bladder carcinogenesis. Within a same patient genomic profile showed high agreement between tumors and their respective recurrences, i.e., tumors from the same patient showed a large number of common losses and gains. The high similarities of genomic alterations in successive tumors from the same patient suggest that a stable genomic profile was established in UBCs and their recurrences. Besides, during the "free‐of‐neoplasia" intervals, negative urinary bladder washes were submitted to Fluorescent in situ Hybridization (FISH) to detect quantitative alterations in centromeres 7 (n=21 samples), 17 (n= 21) and 9p21 (n=36). No numerical alterations... (Complete abstract click electronic access below) / Doutor

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Os microRNAs (miRNAs, miRs) são pequenos RNAs não codificadores presentes em diferentes organismos. Esses RNAs regulam a tradução de genes alvos por meio de ligação seqüência-específica a RNAs mensageiros (mRNAs). Dependendo do grau de complementaridade, podem inibir a tradução e/ou induzir a degradação desses mRNAs. No presente estudo, foi investigado por PCR em tempo real o padrão de expressão de quatro microRNAs (miR-21, -205, -342 e let-7a ) em quatro linhagens celulares derivadas de tumores da cavidade oral e da faringe (FaDu, Hep-2, SCC9 e UM-SCC-38), em queratinócitos orais normais e em amostras de tumor e margens cirúrgicas pareadas de 34 pacientes com carcinomas epidermóides de cabeça e pescoço (CECP). Foi também investigada a correlação da expressão dos MiRs de interesse com as características clinicopatológicas de pacientes com CECP. Nas linhagens celulares, os níveis dos miRs foram similares ou mais baixos que os de queratinócitos normais, ou os miRs não se expressaram. Somente o miR-342 mostrou níveis elevados na linhagem FaDu. Em células Hep-2 tratadas com estradiol, a expressão de miR-let-7a mostrou-se reduzida. Em tumores primários, níveis baixos de miR-let-7a foram observados em carcinomas de soalho de boca e laringe. A expressão de miR-21, -205 e -342 mostrou grande variabilidade entre as amostras e foi reduzida em um dos sítios anatômicos. Não foi observada correlação entre a expressão dos miRs e as características clinicopatológicas dos pacientes com CECP. A análise de três genes alvo candidatos (LYZ, MGLL e SPRR3) mostrou, em carcinomas de soalho de boca e laringe, associação positiva entre a expressão de miR-let-7a e de seu alvo predito MGLL, uma lipase que pode favorecer o fenótipo maligno aumentando os níveis de ácidos graxos livres e sinais lipídicos oncogênicos. O significado dessa associação não pode ser deduzida dos experimentos realizados pelo presente trabalho. / MicroRNAs (miRNAs, miRs) are small, non-coding RNAs present in different organisms. They regulate the translation of target genes through sequence specific binding to mRNA. Depending on the degree of sequence complimentary, they can inhibit translation and/or degradation of target mRNAs In the present study, we used real time PCR to investigate the expression pattern of four microRNAs (miR-21, -205, -342 e let-7a ) in four cell lines derived from tumors of oral cavity and pharinx (FaDu, Hep-2, SCC9 e UM-SCC-38), in normal oral keratinocytes and in matched tumor / surgical margin samples from 34 patients with head and neck squamous cell carcinomas (HNSCC). We also aimed to correlate the miR expression with the clinicopathological features in HNSCC. In cell lines, the miR levels were similar or lower than those in normal keratinocytes, or even absent. Only miR-342 showed high levels in FaDu cell line. In Hep-2 cells treated with estradiol, miR-let-7a expression was reduced. In primary tumors, low miR-let-7a levels were observed in floor of the mouth and larynx carcinomas. The expression of miR-21, -205 and -342 showed high variability between samples and was reduced in one anatomical site. No correlation was observed between miR expression and clinopathological features of head and neck cancer patients. The analysis of three potential target genes (LYZ, MGLL e SPRR3) showed, in floor of the mouth and larynx carcinomas, a positive correlation between the expression of miR-let-7a and its predicted target gene MGLL, a lipase that may support the malignant phenotype by increasing levels of free fatty acids and oncogenic lipid signals. The meaning of such association was not clear from our data.