Defining the clinical value of circulating splicing factors in prostate cancer: SRRM1 as a novel predictive biomarker and exploitable therapeutic target

Abstract

Prostate cancer (PCa) is the second most common cancer among men worldwide. The main screening tool remains the prostatic specific antigen (PSA), which shows significant limitations including poor sensitivity/specificity. Therefore, establishing accurate non-invasive diagnostic biomarkers remains an unmet clinical need in PCa. In this context, the splicing process dysregulation represents a PCa hallmark. Herein, plasma SNRNP200, SRSF3, and SRRM1 levels, previously identified to play a pathophysiological role in PCa, were determined in control individuals (n=40) and PCa patients (n=166). We found that plasma SNRNP200 and SRRM1 levels were elevated in PCa patients and discriminated between control individuals and PCa patients. High plasma SRRM1 levels were associated with a shorter castration-resistant PCa-free survival and correlated with Androgen-Receptor (AR)/AR-splicing variant V7 expression levels and activity in PCa tissues. Therefore, the functional and molecular effects of in-vivo SRRM1 silencing were then tested in 22Rv1-derived xenograft tumors. In-vivo SRRM1 silencing reduced aggressiveness features and altered AR/AR-V7 activity. Altogether, our data reveal that SRRM1 holds potential as a non-invasive diagnostic and prognostic biomarker, and novel therapeutic target in PCa, offering a clinically relevant opportunity worth to be explored in humans.