Abstract
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.
Highlights
Prostate cancer (PCa) is the second most diagnosed cancer type and the fifth cause of death by cancer among males worldwide[1]
We demonstrated that C-terminal binding protein 1 (CTBP1) decreases the in vitro adhesive capabilities of a panel of PCa cell lines through the modulation of genes like Cadherin 1 (CDH1), Integrin Subunit Beta 4 (ITGB4), and Vimentin (VIM) among others
CTBP1 regulates expression of mRNAs and miRNAs involved in cell adhesion on a PC3 and Metabolic syndrome (MeS) in vivo model We previously reported a mice model of PCa and
Summary
Prostate cancer (PCa) is the second most diagnosed cancer type and the fifth cause of death by cancer among males worldwide[1]. Metabolic syndrome (MeS) is one of the most widely prevailing health concerns worldwide. It is a cluster of pathophysiological disorders whose diagnose requires the detection of, at least, three of the following factors: visceral adiposity, high triglycerides, low-high density lipoprotein (HDL) cholesterol levels, high-blood pressure, and elevated fasting glucose levels[4]. Lifestyle, and genetic background affect MeS, there is an increasing body of evidence showing that these factors play a crucial role in PCa risk and progression[6,7,8].
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