RESUMO
BACKGROUND: Changes in cellular metabolism are now recognized as potential drivers of cancer development, rather than as secondary consequences of disease. Here, we explore the mechanism by which metabolic changes dependent on aldehyde dehydrogenase impact cancer development. METHODS: ALDH7A1 was identified as a potential cancer gene using a Drosophila in vivo metastasis model. The role of the human ortholog was examined using RNA interference in cell-based assays of cell migration and invasion. 1H-NMR metabolite profiling was used to identify metabolic changes in ALDH7A1-depleted cells. Publically available cancer gene expression data was interrogated to identify a gene-expression signature associated with depletion of ALDH7A1. Computational pathway and gene set enrichment analysis was used to identify signaling pathways and cellular processes that were correlated with reduced ALDH7A1 expression in cancer. A variety of statistical tests used to evaluate these analyses are described in detail in the methods section. Immunohistochemistry was used to assess ALDH7A1 expression in tissue samples from cancer patients. RESULTS: Depletion of ALDH7A1 increased cellular migration and invasiveness in vitro. Depletion of ALDH7A1 led to reduced levels of metabolites identified as ligands for Peroxisome proliferator-activated receptor (PPARα). Analysis of publically available cancer gene expression data revealed that ALDH7A1 mRNA levels were reduced in many human cancers, and that this correlated with poor survival in kidney and liver cancer patients. Using pathway and gene set enrichment analysis, we establish a correlation between low ALDH7A1 levels, reduced PPAR signaling and reduced patient survival. Metabolic profiling showed that endogenous PPARα ligands were reduced in ALDH7A1-depleted cells. ALDH7A1-depletion led to reduced PPAR transcriptional activity. Treatment with a PPARα agonist restored normal cellular behavior. Low ALDH7A1 protein levels correlated with poor clinical outcome in hepatocellular and renal clear cell carcinoma patients. CONCLUSIONS: We provide evidence that low ALDH7A1 expression is a useful prognostic marker of poor clinical outcome for hepatocellular and renal clear cell carcinomas and hypothesize that patients with low ALDH7A1 might benefit from therapeutic approaches addressing PPARα activity.
Assuntos
Aldeído Desidrogenase/genética , Carcinoma Hepatocelular/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Neoplasias Hepáticas/genética , Receptores Ativados por Proliferador de Peroxissomo/genética , Carcinoma Hepatocelular/patologia , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Renais/patologia , Ligantes , Neoplasias Hepáticas/patologia , RNA Mensageiro/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética , Transcrição Gênica/genéticaRESUMO
A 75-year-old male was diagnosed with renal mass at a computed tomography during an examination for extended abdominal girth. A large mesenterical cyst was also detected. The patient had infrequent voiding, which he had trained over many years as a taxi driver. A basic physical examination led to suspect urinary retention. His creatinine level was normal and he had no hydronephrosis. A renography showed equal function, but prolonged bilateral outflow. The volume extracted by urethral catheter passed 15 l. Absence of hydronephrosis and normal S-creatinine level has not been described in chronic urinary retention of this extent. Hydronephrosis is seen, but in much smaller volume of retention. Infrequent voiding is easily diagnosed. Urinary retention should be suspected when finding median cystic processes.