A PSCA/PGRN - NF-κB - Integrin-α4 axis promotes prostate cancer cell adhesion to bone marrow endothelium and enhances metastatic potential

Distant metastasis, predominantly to bone, is the leading cause of morbidity and mortality in prostate cancer (PCa). However, the mechanisms underlying PCa metastases remain unknown. PCa cells exhibited the discrete adhesion to bone marrow endothelial cells (BMECs), resulting in osteotropic metastasis. Prior data showed an increased metastatic propensity of prostate stem cell antigen (PSCA)-positive PCa cells. The current study sought to characterize the roles of PSCA in the adhesion of PCa cells to BMECs. Cell adhesion was assessed using the adhesion assay and transendothelial migration. The expression and regulation of integrins were evaluated by qRT-PCR, western blot, promoter-luciferase activity and chromatin immunoprecipitation (ChIP). Functionally, the potential interacting partners of PSCA in PCa cells were identified by co-immunoprecipitation and MS analysis. The association of PSCA expression with bone metastasis was further analyzed in vivo model and PCa patients. We found that overexpression of PSCA enhanced the adhesion capability of PCa cells to BMECs through up-regulating integrin-α4 expression, concurrent with transcriptionally activated NF-κB. Growth factor progranulin (PGRN) was identified as a potential interacting partner of PSCA in PCa cells. Functional studies showed that down-regulation of PGRN and PSCA with siRNAs in PCa cells significantly suppressed the integrin-α4 expression and the adhesion to BMECs in vitro, respectively, which were restorable by exogenous PGRN. Importantly, PSCA depletion significantly reduced tumors presence in the bone of a mouse model. Furthermore, PSCA expression is elevated in PCa tissue, and significantly associated with increased Gleason score, advanced stage, bone metastases and poor prognosis in PCa patients. We conclude that PSCA/PGRN promoted the adhesion of PCa cells to BMECs through NF-κB/integrin-α4 pathways, to facilitate metastases. Implications: These findings suggest PSCA/PGRN as a potential therapeutic target for PCa metastases, especially for bone metastasis.