Abstract
Current outcome prediction markers for localized prostate cancer (PCa) are insufficient. The impact of the lipid-modifying Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3B) in PCa is unknown. Two cohorts of patients with PCa who underwent radical prostatectomy (n = 40, n = 56) and benign prostate hyperplasia (BPH) controls (n = 8, n = 11) were profiled for SMPDL3B expression with qRT-PCR. Publicly available PCa cohorts (Memorial Sloane Kettering Cancer Centre (MSKCC; n = 131, n = 29 controls) and The Cancer Genome Atlas (TCGA; n = 497, n = 53 controls)) served for validation. SMPDL3B’s impact on proliferation and migration was analyzed in PC3 cells by siRNA knockdown. In both cohorts, a Gleason score and T stage independent significant overexpression of SMPDL3B was seen in PCa compared to BPH (p < 0.001 each). A lower expression of SMPDL3B was associated with a shorter overall survival (OS) (p = 0.005) in long term follow-up. A SMPDL3B overexpression in PCa tissue was confirmed in the validation cohorts (p < 0.001 each). In the TCGA patients with low SMPDL3B expression, biochemical recurrence-free survival (p = 0.011) and progression-free interval (p < 0.001) were shorter. Knockdown of SMPDL3B impaired PC3 cell migration but not proliferation (p = 0.0081). In summary, SMPLD3B is highly overexpressed in PCa tissue, is inversely associated with localized PCa prognosis, and impairs PCa cell migration.
Highlights
Prostate cancer (PCa) is the most common solid tumor entity in men in developed countries [1,2]
We identified a number of potential protein biomarkers for high-risk prostate cancer (PCa) by proteomic profiling of PCa cells and their extracellular vesicles (EVs) combined with a screening of publicly available databases [3]
AAfftteerr 4488 hh ooff growth, the wound area of the cells treated with siSMPDL3B was 0.264 ± 0.116 compared to siRNAs were used as negative control (siCtrl) at 0.079 ± 0.054, (p= 0.0081, Figure 4a,b)
Summary
Prostate cancer (PCa) is the most common solid tumor entity in men in developed countries [1,2]. Aggressive PCa tumors on the other hand quickly metastasize to regional lymph nodes and the skeleton This results in a fatal disease state that requires a long and demanding therapy. Watanabe et al identified SMPDL3B as potential marker for therapeutic response in rituximab-based immuno-suppressive therapy in pediatric patients with intractable kidney disease with proteinuria [11]. This approach is mainly based on the findings of Heinz et al, who first described SMPDL3B as a negative regulator of innate immunity via reduction of Toll-like receptor function on macrophages [8]. These results were validated in current, publicly available PCa expression data sets, and in vitro analyses were performed in a PCa cell line
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