HEME-OXYGENASE 1 (HO-1) PROMOTES MESENCHYMAL TO EPITHELIAL TRANSITION THROUGH N-CADHERIN SIGNALING IN PROSTATE CANCER

LAGE VICKERS, SOFIA; BIZZOTO, JUAN; PAEZ ALEJANDRA; ORTIZ, EMILIANO G.; COTIGNOLA, JAVIER; VAZQUEZ ELBA; GUERON GERALDINE

CABA

Congreso; LXII Reunión Anual de la Sociedad Argentina de Investigación SAIC; 2017

SAIC

Castration resistant prostate cancer (CRPC) is one of the most important clinical challenges in prostate cancer (PCa) therapy. Epithelial-mesenchymal transition (EMT) plays a critical role in CRPC thus, therapeutic targeting of EMT has the potential to open new avenues in the treatment paradigm of CRPC reversing the invasive mesenchymal phenotype to a more differentiated tumor epithelial phenotype. We have previously shown the strong anti-tumoral action exerted by heme oxygenase 1 (HO-1) in PCa. However its association with EMT is still poorly elucidated. For this purpose we carried out a comprehensive RNA-Seq analysis to compare EMT associated gene expression profiles between PCa cells overexpressing HO-1 pharmacologically (hemin treatment) or genetically (transfected with pcDNA3HO-1 vector) and their respective controls. The obtained EMT signature genes modulated by HO-1 consisted of both epithelial and mesenchymal state-associated mRNAs. The Gene Ontology classifications reflected as the top cellular localization annotations: cell surface, extracellular, or membrane-bound. The top biological processes were cell locomotion and adhesion, extracellular structure organization, embryonic organ morphogenesis and ion homeostasis. Among the identified mesenchymal cell state-associated factors, HO-1 down-regulation of N-Cad, B-catenin, Lef1, ITGA, RHOA, DVL1 and LEF1 mRNAs displayed the most significant altered genes. In particular, HO-1 was able to regulate both up- and downstream N-Cad signaling pathways involving Notch-4, B1 integrin, SMAD7, CDC2, Twist and FN1. N-cad is highly implicated in bone formation and metastasis and HO-1 regulation also displayed significant alterations of Frizzled, Dsh and CDH2 mRNA expression levels. Results were further validated by RTqPCR.This study may cast a new light on CRPC treatment highlighting a multifaceted role for HO-1 in altering EMT signaling, supporting it as a potential therapeutic target for the metastatic disease.Keywords: EMT, prostate cancer.