ECE2022 Oral Communications Oral Communications 6: Endocrine-Related Cancer (6 abstracts)
Translational evidence for splicing factor RBM22 as a novel prognostic biomarker and therapeutic target in prostate cancer
Prudencio Sáez-Martínez 1,2,3,4 , Juan M Jiménez-Vacas 1,2,3,4 , Antonio J Montero-Hidalgo 1,2,3,4 , Ana D Rosa-Herencia 1,2,3,4 , Vicente Herrero-Aguayo 1,2,3,4 , Antonio J León-González 1,2,3,4 , Rafael Sánchez-Sánchez 1,3,5 , Teresa González-Serrano 1,3,5 , Enrique Gómez-Gómez 1,3,6 , Manuel D Gahete 1,2,3,4 & Raúl M Luque 1,2,3,4
1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); 2Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain; 3Reina Sofia University Hospital (HURS), 14004 Cordoba, Spain; 4CIBER Physiopathology of Obesity and Nutrition (CIBERobn), 14004 Cordoba, Spain; 5Anatomical Pathology Service, HURS/IMIBIC, 14004 Cordoba, Spain.; 6Urology Service, HURS/IMIBIC, 14004 Cordoba, Spain
Prostate cancer (PCa) is one the leading causes of cancer-related deaths among men in developed countries. Therefore, identification of novel molecular and therapeutic approaches to tackle this pathology are urgently needed. In this scenario, our group has recently reported that elements of the cellular machinery controlling alternative splicing processes might be used as potential novel therapeutic tools against PCa and castration-resistant PCa (CRPC). In this context, RBM22 has been identified as a key spliceosome component, playing a crucial role for normal development; however, the potential dysregulation and functional role of RBM22 in cancer still remain unknown. Here, we identify for the first time a profound downregulation of RBM22 (at mRNA/protein-levels) in two well-characterized cohorts of PCa patients, compared to non-tumor control samples. Notably, RBM22 levels were inversely associated to key clinical aggressiveness features in PCa (i.e. extraprostatic extension and perineural invasion). These results were confirmed in two additional, independent in silico human cohorts. Overexpression of RBM22 in PCa cells decreased aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere- and colony-formation, etc.), and drastically decreased tumor development and progression in vivo (using a preclinical mouse model), which would underlie a relevant direct association of lower RBM22 levels with enhanced tumor progression. These results were corroborated using the TRAMP mouse model, wherein gradual reduction of RBM22 from prostatic intraepithelial neoplasia to moderately differentiated PCa and to poorly differentiated PCa was observed. These actions are likely mediated through the modulation of key signaling pathways (i.e. cycle-apoptosis, PI3K pathways, etc.) and critical molecular regulators (i.e. MYC, MCYN and E2F), and may also involve the alteration of alternative splicing events of key genes involved in these pathways. Therefore, our study demonstrates for the first time that RBM22 plays a critical functional role in the pathophysiology of PCa and suggests that targeting negative regulators of RBM22 could represent a novel therapeutic strategy to tackle this devastating pathology.
Fundings: MINECO (PID2019-105564RB-I00/FPU16-06190/FPU17-00263/FPU18-02485), Junta de Andalucía (BIO-0139/PI-0152-2019) and CIBERobn.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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