INVESTIGADORES
DE SIERVI Adriana
congresos y reuniones científicas
Título:
CtBP1 expression depletion on primary tumor impairs development of spontaneous metastases on a prostate cancer and metabolic syndrome model.
Autor/es:
DALTON GN; MASSILLO CL; SCALISE G; PORRETTI J; FARRÉ PL; PAEZ A; GUERON G; DE LUCA P; DE SIERVI A
Lugar:
Bariloche
Reunión:
Congreso; Fourth ?South American Spring Symposium in Signal Transduction and Molecular Medicine? (SISTAM 2018); 2018
Institución organizadora:
SISTAM
Resumen:
About 20 % of prostate cancer (PCa) cases will progress to metastatic disease, and at this stage, it turns out incurable due to a lack of therapies. Hence, the need to identify new actionable targets is crucial. Metabolic syndrome (MeS) is a disorder that increases PCa risk and aggressiveness. C-terminal Binding Protein (CtBP1) is a transcriptional corepressor that is activated by NADH binding, and we previously determined that it is a novel molecular link for PCa and MeS. We found that CtBP1 diminished cell adhesion, repressed epithelial marker CDH1 and induced mesenchymal marker VIM. The aim of this work was to investigate MeS/CtBP1 impact over PCa progression from in situ prostate carcinoma to metastases. RNA isolated from xenografts generated on MeS mice from CtBP1 depleted PC3 cells (PC3.shCtBP1) or control (PC3.PGIPZ) was hybridized to a miRNA expression microarray (Affymetrix). We identified a list of 11 miRNAs regulated by CtBP1 relevant to PCa progression. To investigate CtBP1 role in spontaneous PCa metastasis, NOD scid gamma (NSG) mice were fed with control or high fat diets during 12 weeks to induce MeS. Then PC3.shCtBP1 or PC3.PGIPZ cells were injected s.c. on MeS and control animals. No significant differences in body weight between treatments was observed; however 30 days after cell inoculation all mice showed 20% weight loss. Mice were sacrificed and tumors, lungs and livers were collected for further analysis. Using human specific GAPDH primers and RT-qPCR, we found that CtBP1 depletion decrease lung metastases in the MeS group. H&E staining from lung sections showed the lowest number and size of metastatic foci in CtBP1 depleted xenografts generated on MeS mice. We also detected circulating miRNA levels on mice and PCa patient serum samples with or without MeS identifying many candidates for further analysis as biomarkers of PCa/MeS. Our study uncovers for the first time the role of CtBP1 in PCa progression and its molecular targets in MeS.