Endocrine Abstracts (2017) 49 EP790 | DOI: 10.1530/endoabs.49.EP790

Altered expression of the components of the splicing machinery is associated to increased malignancy and expression of aberrant splicing variants in prostate cancer

Juan M Jiménez-Vacas1, Manuel D Gahete1, Sergio Pedraza-Arévalo1, Mercedes del Río-Moreno1, Daniel Hormaechea-Agulla1, Enrique Gómez-Gómez1,2, Julia Carrasco-Valiente2, María del Mar Moreno3, María José Requena-Tapia2, Justo P Castaño1 & Raúl M Luque1

1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC); Reina Sofia University Hospital (HURS); Department of Cell Biology, Physiology and Immunology, University of Cordoba (UCO); CIBER Physi, Cordoba, Spain; 2Service of Urology, HURS/IMIBIC, Cordoba, Spain; 3Service of Anatomical Pathology, HURS/IMIBIC, Cordoba, Spain.

: Prostate cancer (PCa) is the most common cancer among men in developed countries. Unfortunately, the heterogeneity of this malignancy hinders the finding of new biomarkers and therapeutic tools. A potential factor contributing to PCa is alternative splicing, which can generate the appearance of oncogenic variants involved in PCa aggressiveness. Thus, we hypothesized that the alteration of the splicing machinery (spliceosome components and splicing factors (SFs)) could be associated to the expression of tumorigenic splicing variants and malignancy of PCa. Accordingly, we characterized the expression pattern of key components of the major (n=13) and minor spliceosome (n=4) and associated SFs (n=28) in 51 PCa biopsies and 15 normal prostates, by using a microfluidic-based qPCR-array. The results revealed a downregulation of two key components of the spliceosome responsible for the recognition of and binding to the branching site of the target introns (RNU2 and RNU12) in PCa samples compared to controls, which might explain the prevalence of intron retention events found in PCa. In addition, expression of other components of the minor spliceosome (i.e. RNU11, RNU4atac or PRPF8) was also significantly reduced in PCa, suggesting a profound dysregulation of the minor spliceosome function and a consequent alteration in the processing of U12-introns. Furthermore, this analysis also revealed a marked alteration of certain SFs (i.e. SRSF5, SRSF9, MAGOH or TIA1) in PCa, whose expression was associated with the expression of relevant splicing variants (i.e. In1-ghrelin variant) and with malignancy features (metastasis, PSA levels, etc.). Finally, functional assays (proliferation, migration, etc.) with PCa cell lines confirmed the pathophysiological role of some of these SFs. Altogether, these results indicate that the splicing machinery is drastically dysregulated in PCa, which could help to explain the predominance of intron retention events and the appearance of tumorigenic splicing variants in this pathology, providing novel tools to develop diagnostic markers or therapeutic targets.