INVESTIGADORES
RODRIGUEZ SEGUI Santiago Andres
congresos y reuniones científicas
Título:
CtBP1 is implicated in prostate tumor development in a metabolic syndrome-like disease in vivo model
Autor/es:
MOIOLA, C.P.; DE LUCA, P.; ZALAZAR, F.; RODRÍGUEZ SEGUÍ, S.A.; COTIGNOLA, J.; MEISS, R.; VAZQUEZ, E.S.; DALTON, N.; LABANCA, E.; GARDNER, K.; DE SIERVI, A.
Lugar:
California
Reunión:
Congreso; American Association for Cancer Research (AACR) Annual Meeting 2014; 2014
Institución organizadora:
American Association for Cancer Research (AACR)
Resumen:
Clinical and epidemiological data suggest
that obesity is associated with more aggressive forms of prostate cancer
(PCa),
poor prognosis and increased mortality. In
addition, high calorie intake decreases intracellular NAD+/NADH ratio.
C-terminal
Binding Protein 1 (CtBP1) is a transcription
repressor of several important tumor suppressor genes and is activated
by NADH
binding. The aim of this work was to assess the
effect of a high fat diet (HFD) and CtBP1 expression modulation over PCa
tumor
development in a murine xenograft model.
We developed a metabolic syndrome-like
disease in vivo model. Male nude mice fed with HFD or control diet (CD)
for 16 weeks
showed hypercholesterolemia, low testosterone serum
levels, liver steatosis and glomeruli enlargement with edema at the
kidney
ephitelium collecting duct. In addition, at week 12
of diet, prostate tumor PC3 cells stable transfected with shCtBP1 or
control
(pGIPZ) plasmids were s.c. inoculated into randomly
divided mice groups. No significant differences were observed in tumor
growth on CD fed mice; however, we found that only
60 % of HFD fed mice inoculated with CtBP1 depleted cells developed a
tumor;
even more these tumors were significantly smaller
than those generated by PC3.pGIPZ control xenografts. Furthermore, CtBP1
depletion in xenograft tumors was validated by IHQ
and RT-qPCR.
Genome-wide expression profiles (HUGENE
ST1.0 Affymetrix) from PC3.shCtBP1 versus PC3.pGIPZ HFD fed mice tumors
showed 823
genes differentially expressed (1.5 fold change and
p < 0.05). By biological process GO classification, we found that
most
of these genes correspond to cell adhesion,
metabolic process, apoptosis and cell cycle among others GO terms. In
addition,
we performed Gene Set Enrichment Analyses (GSEA)
from our expression datasets and contrasted our results using MSigDB (C2
and C5 gene sets collection). We identified gene
sets associated with metabolic and cellular processes. Interestingly,
E-cadherin
(CDH1) and aromatase (CYP19A1) expression were
up-regulated in CtBP1 depleted tumors, and we validated this evidence by
RT-qPCR.
Our results suggested that metabolic syndrome-like
diseases and CtBP1 expression might cooperate to PCa tumor development.
Hence, CtBP1 expression might be considered for PCa
management and therapy in the subset of patient with metabolic
syndromes.