RESUMO
BACKGROUND: SPRED1 and 2 are key negative regulators of MAPK signalling in mammalian cells. Here, we investigate the expression and functional role of SPREDs in prostate cancer. METHODS: A transcriptome bank of microdissected grade-specific primary cancers was constructed and interrogated for transcript expression of prostate cancer genes, known negative signalling regulators as well as SPRED1 and 2. The effect of SPRED2 manipulation was tested in in vitro assays. RESULTS: In a panel of 5 benign glands and 15 tumours, we observed concomitant downregulation of the negative regulators SEF and DUSP1 in tumours with increasing Gleason grade. Profiling in the same cohorts revealed downregulation of SPRED2 mRNA in tumours compared with benign glands (P<0.05). By contrast, SPRED1 expression remained unchanged. This observation was further validated in two additional separate cohorts of microdissected tumours (total of n=10 benign and n=58 tumours) with specific downregulation of SPRED2 particularly in higher grade tumours. In functional assays, SPRED2 overexpression reduced ERK phosphorylation and inhibited prostate cancer cell proliferation and migration in response to different growth factors and full-media stimulation (P<0.001). Conversely, SPRED2 suppression by siRNA enhanced the mitogenic response to growth factors and full media (P<0.001). CONCLUSION: These data suggest first evidence that SPRED2 is downregulated in prostate cancer and warrants further investigation as a potential tumour-suppressor gene.
Assuntos
Fosfatase 1 de Especificidade Dupla/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Receptores de Interleucina/genética , Proteínas Repressoras/genética , Proteínas Adaptadoras de Transdução de Sinal , Western Blotting , Movimento Celular , Proliferação de Células , Estudos de Coortes , Regulação para Baixo , Fosfatase 1 de Especificidade Dupla/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Gradação de Tumores , Prognóstico , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais CultivadasRESUMO
PURPOSE: Primary androgen deprivation therapy (PADT) is an important treatment modality for men with localized or locally advanced prostate cancer and without bone metastasis. There is, however, a lack of data on the biochemical relapse (BR) outcomes in these patients. Here, we studied the outcome of a contemporary series of men treated by PADT and investigated predictive risk factors for BR. METHODS: One hundred and fifty-five patients treated by PADT formed the initial study cohort, and BR outcomes in this group were reviewed. The outcomes of men with bone scan negative disease were specifically analysed. The predictive value of a panel of clinical risk factors for BR was evaluated using univariate and multivariate analysis. The results were further validated in a separate cohort of patients without bone metastasis from a second institution (n = 84). RESULTS: Median follow-up was 70 months. In the first study cohort, 109/155 men (70%) had bone scan negative disease. In these patients, only 45% developed BR during the follow-up period with only 28% relapsing within 5 years of initiating PADT. Key-independent factors predicting BR were a high PSA nadir (p = 0.001) and a shorter time to nadir (p < 0.001). A nadir of ≤0.1 ng/ml and time to nadir of >24 months specifically identified men with a very good outcome from PADT. In a second-independent cohort, very similar overall and 5-year BR rates were observed in men without bone metastasis (39 and 35%, respectively). PSA nadir thresholds identified in the first cohort were again able to define a good prognostic group in this re-test cohort (p = 0.005 and p = 0.01, respectively). CONCLUSION: Men treated by PADT and without bone metastasis can have very durable responses to PADT with the majority remaining BR free at 5 years. PSA nadir and time to nadir are key predictors of a good outcome in this group.
