RAB27A, RAB27B and VPS36 are downregulated in advanced prostate cancer and show functional relevance in prostate cancer cells

Abstract

Paracrine and long-range signaling via extracellular vesicles, such as exosomes and microvesicles, is deemed crucial for tumorigenesis, invasion and spread of solid tumors. The ESCRT machinery (endosomal sorting complexes required for transport) and Rab-proteins act as key players in vesicular trafficking and secretion. Yet, their role in prostate cancer (PCA) is unknown. Therefore, this study aimed to elucidate the relevance of these components in PCA. In silico reanalysis of genes with known involvement in vesicular trafficking and secretion in an existing microarray dataset revealed low expression of RAB27A, RAB27B and VPS36 to be predictive for reduced BCR-free survival in patients with localized PCA (p=0.033, 0.025 and 0.005). In the same microarray dataset underexpression of RAB27A, RAB27B and VPS36 was seen in distant metastases (p<0.001; p=0.003; p<0.001). This was consistent in two further microarray datasets. qRT-PCR-validation in two independent cohorts of PCA specimens (n=90) showed low expression of VPS36 in PCA tissue (p=0.023), especially in castration-resistant tumors (p=0.002). In all five datasets there were significant correlations between the expression of at least two of the candidates.