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Doctoral Thesis
DOI
https://doi.org/10.11606/T.5.2021.tde-23082021-111641
Document
Author
Full name
Paulo Afonso de Carvalho
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2020
Supervisor
Committee
Leite, Katia Ramos Moreira (President)
Chade, Daher Cezar
Cordeiro, Mauricio Dener
Cunha, Isabela Werneck da
Title in Portuguese
Análise de expressão de transportadores de monocarboxilato MCT1, MCT2 e MCT4, da chaperona CD147 e das proteínas CD44, HIF-1alfa, CA-IX e GLUT1 no carcinoma de células renais do tipo células claras
Keywords in Portuguese
Carcinoma de células renais
HIF- 1alfa.
Imuno-histoquímica
Metabolismo energético
Prognóstico
Proteína supressora de tumor von Hippel-Lindau
Abstract in Portuguese
INTRODUÇÃO: O carcinoma de células renais é a neoplasia urológica mais letal e responsável por 2-3% de todos os cânceres diagnosticados. O subtipo células claras (CCRcc) é o mais comum, correspondendo a 75% dos casos. A maioria se caracteriza pela inativação da proteína supressora de tumor von Hippel-Lindau (pVHL), que leva à desregulação do gene HIF-1? (fator induzido pela hipóxia 1?). HIF-1? é um fator de transcrição que induz a expressão de genes responsáveis pelo metabolismo energético celular. OBJETIVO: Determinar o padrão de imunoexpressão das proteínas: HIF-1?, MCT1, MCT2, MCT4, CD44, CD147, GLTU1 e CA-IX e correlacioná-los com sobrevida global, sobrevida câncer específica e com fatores prognósticos clássicos em pacientes portadores de CCRcc não metastático. MÉTODOS: Neste estudo retrospectivo com 207 pacientes com CCRcc localizado, foi analisada a expressão imunohistoquímica, das proteínas previamente citadas em micro arranjo tecidual (TMA). A expressão de cada proteína foi estratificada em 4 grupos (0, 1, 2 e 3), de acordo com a intensidade da coloração, por patologista experiente (KRML) e os níveis de expressão foram relacionados aos fatores prognósticos clássicos do CCRcc, sobrevida global e câncer específica. RESULTADOS: Ao estratificar a imunoexpressão das proteínas em dois grupos (expressão 0 + 1 e 2 + 3), a análise uni variada mostrou associação entre a expressão de MCT1 e a presença de sintomas (p=0,0001), grau nuclear de Fuhrman (p=0,0059), invasão da gordura perirrenal (p=0,0024), invasão da veia renal (p=0,002), presença de necrose (p=0,0001), invasão da cápsula (p=0,0135), tamanho tumoral (p<0,0001) e estádio patológico pT (p<0,0001). Em relação a sobrevida, a análise uni variada mostrou que a maior expressão das proteínas MCT1 e CD147 correlacionou-se com menor sobrevida global (Log-Rank, p=0,0003 e p=0,0004) e menor sobrevida câncer específica (Log-Rank, p<0,0001 e p=0,0002) respectivamente. Na análise multivariada a maior expressão de CD147 se correlacionou com a menor sobrevida global (p=0,0448). A maior expressão de MCT1 associou-se à menor sobrevida global (p=0,0281) e menor sobrevida câncer específica (p=0,031). CONCLUSÃO: As expressões das proteínas MCT1 e CD147 são um marcador de prognóstico desfavorável no CCRcc.
Title in English
Evaluation of the immunoexpression of monocarboxylate transporters MCT1, MCT2 and MCT4, CD147 chaperone and CD44, HIF-1alfa, CA-IX and GLUT 1 proteins in clear cell renal cell carcinoma
Keywords in English
Carcinoma renal cell
Energy metabolism
HIF-1alpha.
Immunohistochemistry
Prognosis
Von Hippel-Lindau tumor suppression protein
Abstract in English
INTRODUCTION: Renal cell carcinoma is the most lethal urologic neoplasm, responsible for 2-3% of all cancers. The clear cell variant (ccRCC) is the most common, accounting for 75% of cases. Most are characterized by the inactivation of von Hippel-Lindau tumor suppression protein, which leads to dysregulation of the HIF-1? gene. HIF-1? is a transcription factor that induces the expression of genes responsible for cellular energetic metabolism. OBJECTIVES: To determine the pattern of protein immunoexpression: HIF-1?, MCT1, MCT2, MCT4, CD44, CD147, GLTU1 and CA-IX, and to correlate them with overall survival, specific cancer survival and classic prognostic factors in patients with non-metastatic ccRCC. METHODS: In this retrospective study composed by 207 patients with non-metastatic ccCCR, the immunohistochemistry expression of the previously mentioned proteins was analyzed through the tissue microarray technique (TMA). The expression of each protein was stratified into four groups (0, 1, 2 and 3); according to the staining intensity, by an experienced pathologist (KRML) and expression levels were related to the classic prognostic factors of ccRCC, overall and cancerspecific survival. RESULTS: By stratifying the immunoexpression of the proteins into two groups (expression 0 + 1 and 2 + 3), the univariate analysis showed that the expression of MCT1 correlated with the presence of symptoms (p=0.0001), Fuhrman nuclear grade (p = 0.0059), perirenal fat invasion (p=0.0024), renal vein invasion (p=0.002), presence of necrosis (p=0.0001), capsule invasion (p=0.0135), tumor size (p<0,0001) and pathological stage pT (p<0.0001). There was also correlation between overexpression of MCT1 and CD147 proteins with lower overall survival (Log-Rank, p=0.0003 and p=0.0004) and lower cancer-specific survival (Log-Rank, p<0.0001, and p=0.0002) respectively. In multivariate analysis, the highest expression of CD147 was correlated with the lowest overall survival (p=0.0448). The highest expression of MCT1 was associated with lowest overall survival (p=0.0281) and lowest cancer-specific survival (p=0.031). CONCLUSION: Expression levels of MCT1 and CD147 are independent markers of unfavorable prognosis in ccRCC
 
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Publishing Date
2021-08-23
 
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