RESUMO
The onconeuronal cerebellar degeneration-related antigen Cdr2 is associated with paraneoplastic syndromes. Neoplastic expression of Cdr2 in ovary and breast tumors triggers an autoimmune response that suppresses tumor growth by developing tumor immunity, but culminates in cerebellar degeneration when Cdr2-specific immune cells recognize neuronal Cdr2. We identified Cdr2 as a novel interactor of the hypoxia-inducible factor (HIF) prolyl-4-hydroxylase PHD1 and provide evidence that Cdr2 might represent a novel important tumor antigen in renal cancer. Strong Cdr2 protein expression was observed in 54.2% of papillary renal cell carcinoma (pRCC) compared with 7.8% of clear-cell RCC and no staining was observed in chromophobe RCC or oncocytoma. High Cdr2 protein levels correlated with attenuated HIF target gene expression in these solid tumors, and Cdr2 overexpression in tumor cell lines reduced HIF-dependent transcriptional regulation. This effect was because of both attenuation of hypoxic protein accumulation and suppression of the transactivation activity of HIF-1alpha. pRCC is known for its tendency to avascularity, usually associated with a lower pathological stage and higher survival rates. We provide evidence that Cdr2 protein strongly accumulates in pRCC, attenuates the HIF response to tumor hypoxia and may become of diagnostic importance as novel renal tumor marker.
Assuntos
Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Hipóxia Celular/genética , Linhagem Celular Tumoral , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos , Proteínas do Tecido Nervoso/imunologia , Oxigênio , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Ligação Proteica , Transcrição Gênica , Ativação Transcricional , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
AIMS: The von-Hippel-Lindau (VHL) tumor suppressor is a multifunctional protein. VHL mutations are common in sporadic clear cell renal cell carcinoma (ccRCC). Different mutation types may specifically alter pVHL functions, which have significant impact on gene expression and, consequently, on the disease outcome. The aim of this study was to identify gene expression signatures that correlate with specific VHL gene mutation types in RCC. METHODS: Total RNA and genomic DNA were extracted from 94 frozen clear cell (ccRCC) and 21 papillary RCC (pRCC) specimens from the tumor biobank of Zurich University Hospital. Transcriptome analysis was performed using Affymetrix HG U133A gene chips. All ccRCC tumors were subjected to VHL gene mutation analysis. RESULTS: By applying significance analysis of microarrays genes were identified, which were differentially regulated among the tumor subgroups. Hierarchical clustering based on the expression profile of the most differentially regulated genes resulted in a significant stratification between the two RCC populations. A total of 186 differentially expressed genes were identified by comparing the gene expression profiles of ccRCC with VHL loss-of-function mutations and ccRCC with no gene alterations. CONCLUSIONS: The results clearly argue for a significant influence of VHL mutations on gene expression profiles in RCC.
