Abstract
Abstract Prostate cancer (PCa) is a complex and progressive disease. Under the selective pressure of medical and drug treatment, PCa cells are able to acquire molecular changes that allow them to survive in androgen-deprived conditions and finally cause their host’s death. Inflammation fosters multiple hallmarks of cancer. However, the molecular mechanisms that prime the pathogenesis of cancer-related inflammation 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 in PCa, maintaining homeostasis and counteracting oxidative and inflammatory damage. We have previously documented HO-1 nuclear expression in human primary prostate carcinomas. In PCa cell lines we confirmed that HO-1 overexpression inhibits cell proliferation, migration, and invasion. It also impairs tumor growth in vivo and downregulates the expression of target genes associated with inflammation. Considering the crosstalk between inflammation and cancer progression, our next step sought to identify signaling pathways by which HO-1 could be operating. Towards this end we performed and analyzed RNAseq data on PCa cells overexpressing HO-1 pharmacologically or genetically. Of note, HO-1 significantly upregulated the human myxovirus resistant protein A (Mx1). The clear association between Mx1 expression and cancer remains unknown. In vitro studies revealed that forced expression of HO-1 in PCa cells significantly upregulated 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 downregulation (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, assessing whole-exome and RNAseq data. The most frequent genetic alteration found for MX1 was deletion. RNASeq data also confirmed a significant downregulation 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. Citation Format: Emiliano Ortiz, Alejandra Páez, Nicolás Anselmino, Javier Cotignola, Pía Valacco, Elba Vázquez, Geraldine Gueron. Heme-oxygenase 1 negatively regulates interferon inducible antiviral (mx1) in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B080.
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