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

VAZQUEZ ELBA S.; ANSELMINO NICOLAS; VALACCO PIA; PAEZ ALEJANDRA V.; GUERON GERALDINE; COTIGNOLA JAVIER; EMILIANO G. ORTIZ

Orlando

Congreso; Prostate Cancer: Advances in Basic, Translational, and Clinical Research.; 2017

AACR

Prostate cancer (PCa) is a complex and progressive disease. Under the selectivepressure of medical and drug treatment, PCa cells are able to acquire molecularchanges that allow them to survive in androgen-deprived conditions and finallycause their host?s death. Inflammation fosters multiple hallmarks of cancer.However, the molecular mechanisms that prime the pathogenesis of cancer-relatedinflammation are yet to be deciphered. In this context, heme-oxygenase 1 (HO-1),the rate-limiting enzyme in heme degradation, emerges as a potential target inPCa, maintaining homeostasis and counteracting oxidative and inflammatorydamage. We have previously documented HO-1 nuclear expression in humanprimary prostate carcinomas. In PCa cell lines we confirmed that HO-1overexpression inhibits cell proliferation, migration and invasion. It also impairstumor growth in vivo and down-regulates the expression of target genes associatedwith inflammation. Considering the cross talk between inflammation and cancerprogression, our next step sought to identify signaling pathways by which HO-1could be operating. Towards this end we performed and analysed RNAseq data onPCa cells overexpressing HO-1 pharmacologically or genetically. Of note HO-1significantly up-regulated the human myxovirus resistant protein A (Mx1). The clearassociation between Mx1 expression and cancer remains unknown. In vitro studiesrevealed that forced expression of HO-1 in PCa cells, significantly up-regulatedMX1 mRNA and protein levels and shifted its localization towards the perinucleararea.To address the relevance of MX1 in PCa we searched the public cancer microarraydatabase, Oncomine. MX1 was ranked by its P-value for every analysis scoring agene rank. We then obtained a median rank (Median P-value rank acrossdatasets) 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 exomeand RNAseq data. The most frequent genetic alteration found for MX1 wasdeletion. RNASeq data also confirmed a significant down-regulation for MX1(P0.05). Moreover, Kaplan-Meier analysis also showed in PCa patients that MX1loss was associated with decreased overall and disease-free survival (P0.05).Overall, HO-1 potentially operates through Mx1, whose expression inverselycorrelates with PCa, depicting its critical role in prostate carcinogenesis.