Prostate cancer is one of the leading causes of mortality in men. The major cause of death in
prostate cancer patients can be attributed to metastatic spread of disease or
tumor recurrence after initial treatment. Prostate
tumors are known to remain undetected or dormant for a long period of time before they progress locoregionally or at distant sites as overt
tumors. However, the molecular mechanism of dormancy is yet poorly understood. In this study, we performed a differential gene expression analysis and identified a gene, Regucalcin (RGN), which promotes dormancy of
prostate cancer. We found that
cancer patients expressing higher level of RGN showed significantly longer recurrence-free and overall- survival. Using a
doxycycline-inducible RGN expression system, we showed that ectopic expression of RGN in prostate
tumor cells induced dormancy in vivo, while following suppression of RGN triggered recurrence of
tumor growth. On the other hand, silencing RGN in LNCap cells promoted its outgrowth in the tibia of mice. Importantly, RGN promoted multiple known hallmarks of
tumor dormancy including activation of
p38 MAPK, decrease in Erk signaling and inhibition of FOXM1 expression. Furthermore, we found that RGN significantly suppressed angiogenesis by increasing secretory miR-23c level in the exosomes. Intriguingly, FOXM1 was found to negatively regulate miR-23c expression in
prostate cancer. In addition, we identified 11 RGN downstream target genes that independently predicted longer recurrence-free survival in patients. We found that expression of these genes was regulated by FOXM1 and/or
p38 MAPK. These findings suggest a critical role of RGN in
prostate cancer dormancy, and the utility of RGN signaling and exosomal miR-23c as
biomarkers for predicting recurrence.