CTBP1 depletion on prostate tumors deregulates miRNA/mRNA expression and impairs cancer progression in metabolic syndrome mice.
Guillermo Nicolás DaltonCintia MassilloGeorgina Daniela ScaliseRocío DucaJuliana PorrettiPaula Lucia FarréKevin GardnerAlejandra PaezGeraldine GueronPaola De LucaAdriana De SierviPublished in: Cell death & disease (2019)
About 20% of prostate cancer (PCa) patients progress to metastatic disease. Metabolic syndrome (MeS) is a pathophysiological disorder that increases PCa risk and aggressiveness. C-terminal binding protein (CTBP1) is a transcriptional corepressor that is activated by high-fat diet (HFD). Previously, our group established a MeS/PCa mice model that identified CTBP1 as a novel link associating both diseases. Here, we integrated in vitro (prostate tumor cell lines) and in vivo (MeS/PCa NSG mice) models with molecular and cell biology techniques to investigate MeS/CTBP1 impact over PCa progression, particularly over cell adhesion, mRNA/miRNA expression and PCa spontaneous metastasis development. We found that CTBP1/MeS regulated expression of genes relevant to cell adhesion and PCa progression, such as cadherins, integrins, connexins, and miRNAs in PC3 xenografts. CTBP1 diminished PCa cell adhesion, membrane attachment to substrate and increased filopodia number by modulating gene expression to favor a mesenchymal phenotype. NSG mice fed with HFD and inoculated with CTBP1-depleted PC3 cells, showed a decreased number and size of lung metastases compared to control. Finally, CTBP1 and HFD reduce hsa-mir-30b-5p plasma levels in mice. This study uncovers for the first time the role of CTBP1/MeS in PCa progression and its molecular targets.
Keyphrases
- cell adhesion
- high fat diet
- prostate cancer
- high fat diet induced
- metabolic syndrome
- insulin resistance
- gene expression
- binding protein
- adipose tissue
- poor prognosis
- stem cells
- squamous cell carcinoma
- end stage renal disease
- small cell lung cancer
- single cell
- chronic kidney disease
- radical prostatectomy
- wild type
- cell therapy
- transcription factor
- newly diagnosed
- dna methylation
- cardiovascular disease
- single molecule
- mesenchymal stem cells
- long non coding rna
- peritoneal dialysis
- skeletal muscle
- squamous cell
- heat shock protein