A PSCA/PGRN–NF-κB–Integrin–α4 Axis Promotes Prostate Cancer Cell Adhesion to Bone Marrow Endothelium and Enhances Metastatic Potential

Abstract Distant metastasis, predominantly to bone, is the leading cause of morbidity and mortality in prostate cancer. However, the mechanisms underlying prostate cancer metastases remain unknown. Prostate cancer cells exhibited discrete adhesion to bone marrow endothelial cells (BMEC), resulting in osteotropic metastasis. Prior data showed an increased metastatic propensity of prostate stem cell antigen (PSCA)–positive prostate cancer cells. The current study sought to characterize the roles of PSCA in the adhesion of prostate cancer 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 prostate cancer cells were identified by coimmunoprecipitation and mass spectrometry (MS) analysis. The association of PSCA expression with bone metastasis was further analyzed in an in vivo model and prostate cancer patients. We found that overexpression of PSCA enhanced the adhesion capability of prostate cancer cells to BMECs through upregulating integrin-α4 expression, concurrent with transcriptionally activated NF-κB. Growth factor progranulin (PGRN) was identified as a potential interacting partner of PSCA in prostate cancer cells. Functional studies showed that downregulation of PGRN and PSCA with siRNAs in prostate cancer 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 prostate cancer tissue, and significantly associated with increased Gleason score, advanced stage, bone metastasis, and poor prognosis in prostate cancer patients. We conclude that PSCA/PGRN promoted the adhesion of prostate cancer cells to BMECs through NF-κB/integrin-α4 pathways, to facilitate metastases. Implications: The findings presented here suggest PSCA/PGRN as a potential therapeutic target for prostate cancer metastases, especially for bone metastasis.