RESUMO
Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked ß-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n = 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n = 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells.
Assuntos
N-Acetilglucosaminiltransferases/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Androgênios/genética , Androgênios/metabolismo , Biomarcadores Tumorais/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Replicação do DNA/efeitos dos fármacos , Hexosaminas/biossíntese , Hexosaminas/genética , Hexosaminas/metabolismo , Humanos , Masculino , Redes e Vias Metabólicas , N-Acetilglucosaminiltransferases/antagonistas & inibidores , N-Acetilglucosaminiltransferases/genética , Neoplasias da Próstata/enzimologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Papillary intralymphatic angioendothelioma is a rare, low-grade neoplasm of lymphatic channels that usually presents intradermally or subcutaneously. We report the case of a 24-year-old male presenting with an isolated intratesticular palpable mass and symptoms of testicular pain. Preoperative ultrasound examination showed an irregular, heterogeneous mass. Subsequent surgery and pathologic assessment revealed a papillary intralymphatic angioendothelioma (PILA), formerly known as Dabska tumor within the lymphatic spaces.
RESUMO
OBJECTIVE: To assess the accuracy of HistoScanning™ (HS) as a visualization tool for preoperative treatment planning for nerve-sparing (NS) radical prostatectomy (RP). PATIENTS AND METHODS: A retrospective study was carried out on 80 patients with prostate cancer undergoing RP from October 2009 to December 2009. All patients underwent a HS procedure 1 day before surgery. Frozen sections (FSs) were performed on each latero-posterior side of the prostate to assess for the presence of cancer. On the HS analysis, the region corresponding to that removed at FS was assessed for suspicious lesions. The size of suspicious lesions within this volume was compared with the FS histopathological analysis. RESULTS: HS results corresponded to a 93% probability of having a negative surgical margin in the FSs. The presence of a HS volume ≥0.2 mL in a specific side was associated with a 3.7 times increased risk of a positive surgical margin at FS. CONCLUSIONS: HS has the potential to assist in the planning of NSRP. Larger, multicentre studies need to be performed for validation of these encouraging results.
