IMPLICATIONS OF HEME-OXYGENASE 1 MODULATION OF INTERFERON INDUCIBLE ANTIVIRAL (MX1) IN PROSTATE CANCER

VAZQUEZ ELBA; ORTIZ EMILIANO GERMAN; VALACCO, PIA; PAEZ, ALEJANDRA VERÓNICA; COTIGNOLA, JAVIER; ANSELMINO, NICOLÁS; GUERON GUERALDINE

CABA

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

SAIC

The principal goal currently within prostate cancer (PCa) research is to unveil markers for early detection of aggressive tumors that are predestined to invade and metastasize. We have previously reported that heme oxygenase-1 (HO-1) exerts an anti-tumoral role in PCa, ascertaining it as a logical target for therapy intervention. HO-1 over-expression impairs tumor growth and angiogenesis in vivo. Considering the cross talk between inflammation, angiogenesis and cancer progression, our next step sought to identify signaling pathways by which HO-1 could be operating. Towards this end we performed and analysed RNAseq data on PCa cells overexpressing HO-1 pharmacologically or genetically. Of note HO-1 significantly up-regulated the human myxovirus resistant protein A (Mx1). In vitro studies revealed that forced expression of HO-1 in PCa cells, significantly up-regulated MX1 mRNA and protein levels and shifted its localization towards the perinuclear area.To address the relevance of MX1 in PCa we searched the public cancer microarray database, Oncomine. MX1 was ranked by its P-value for every analysis scoring a gene rank. We then obtained a median rank (Median P-value rank across datasets) for MX1. The expression profile for MX1 showed a significant down-regulation (fold change 1.5, P0.05) comparing prostate adenocarcinoma vs. normal prostate gland, lying within the 2-19 % of the most consistently low-expressed genes across this comparison. We extended the bioinformatics analysis, using cBioportal, assesing whole exome and RNAseq data. The most frequent genetic alteration found for MX1 was deletion. RNASeq data also confirmed a significant down-regulation for MX1 (P0.05). Moreover, Kaplan-Meier analysis also showed in PCa patients that MX1 loss was associated with decreased overall and disease-free survival (P0.05). Overall, HO-1 potentially operates through Mx1, whose expression inversely correlates with PCa, depicting its critical role in prostate carcinogenesis.