Estudio del efecto celular y metabólico del eje TWEAK/Fn14 en el microambiente del cáncer de próstata

Identificador:  TDX:4113

Handle: https://hdl.handle.net/20.500.11797/TDX4113

Autors:  Altuna Coy, Antonio

Resum:
The main problem with prostate cancer (PCa) is the lack of biomarkers to diagnose aggressive tumors. Different proinflammatory cytokines alter tumor metabolism and the secretion of extracellular vesicles (EVs), modifying their microRNAs cargo (exomiRNAs). TWEAK is a proinflammatory cytokine of the TNF family that is both membrane-bound (mTWEAK) and soluble (sTWEAK) and is implicated in cancer through its receptor, Fn14. We study whether the presence of sTWEAK in the PCa microenvironment alters tumor metabolism and the usefulness of serum sTWEAK levels as a biomarker. The data indicate that decreased serum levels of sTWEAK are independent predictors of PCa. Furthermore, sTWEAK alters lipid metabolism by activating the ERK and AKT pathways via Fn14, regulating the expression of genes involved in de novo lipogenesis or lipolysis, and mobilizing and accumulating lipids in vitro in the PC-3 cell line. On the other hand, we evaluated the effect of sTWEAK on the secretion of VEs. We identified 14 exomiRNAs regulated in vitro by sTWEAK in the LNCaP and PC-3 cell lines. Of these, the expression of exomiR-221-3p, -222-3p and -31-5p was elevated in semen from patients with High Risk PCa compared to those Low Risk, while in urine from High Risk patients the expression of exomiR-193-3p and -423-5p was lower. We designed a model, composed of relative expression seminal levels of exomiR-221-3p and -222-3p and seminal sTWEAK levels, which correctly classifies 87.5% of patients based on aggressiveness. In addition, sTWEAK in vitro regulates two specific targets of exomiR-221-3p related to tumor progression in the PC-3 cell line, transcription factor 12 (TCF12) and Nemo-like Kinase (NLK). In conclusion, the data implicate the TWEAK/Fn14 axis in PCa progression since they alter its metabolism and cellular activity.