Endocrine Abstracts

Introduction

Alternative splicing allows the generation of multiple RNA isoforms from a single pre-RNA molecule, and thereby contributes to a multitude of physiological processes, but can also be involved in many diseases, including cancer. Indeed, disruption of alternative splicing has been linked to key cancer features, such as tumor growth, metastasis and hormone responsiveness and is increasingly regarded as a novel and transversal cancer hallmark. The dysregulation of the splicing machinery could constitute the underlying cause in many of these alterations and, consequently, is an attractive target of study. In this context, it has been previously described that a member of SR splicing factor family, SRSF2, play a relevant role of as an oncodriver in various cancers like hepatocellular carcinoma and myelodysplastic syndromes.

Objective

We aimed to investigate the presence, relevance and potential role as diagnostic/prognostic biomarker and therapeutic target of SRSF2/SC35 in two tumoral pathologies strongly influenced by the patient endocrine-metabolic status: 1) prostate cancer (PCa), the most diagnosed tumors among men worldwide; and 2) pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers.

Methods

The expression of SRSF2 was measured in tumor vs. non-tumor adjacent tissue in a set of 79 PDAC and 45 PCa human samples. The results were validated using publicly available external cohorts. The role of this splicing factor was assessed in vitro by analyzing a set of functional parameters in response to siRNA-induced SRSF2-silencing in various PDAC and PCa cell lines.

Results

Our data revealed that SRSF2 was overexpressed in both tumors and its expression was associated to poor prognosis and relevant malignancy features, including tumor stage, presence of lymph node invasion and/or metastasis, which was confirmed using independent cohorts of patients. SRSF2-silencing significantly reduced cell migration, proliferation, invasion, and colony formation in PDAC and PCa cell lines in comparison with control cells through the alteration of key oncogenic signaling-pathways and the modulation of the expression of relevant genes.

Conclusions

These results suggest a role of the splicing factor SRSF2 in both pancreatic and prostate adenocarcinoma oncogenesis and aggressiveness, thus paving the way to explore its possible value as a biomarker and therapeutic target in both types of cancers.

Funding

MICINN (PID2019-105201RB-I00, PID2019-105564RB-I00, FPU18/02275), Junta de Andalucía (BIO-0139) and CIBERobn.