Evidence for a role of GPRC6A in prostate cancer metastasis based on case-control and in vitro analyses

G protein-coupled receptor, family C, group 6, member A, (GPRC6A) is a prostate cancer (PCa) susceptibility gene and has been shown to regulate PCa progression. However, its role in PCa metastasis is largely unknown. The aim of this study was to confirm the association between GPRC6A and aggressive PCa in a case-control analysis, and to explore the function of GPRC6A in PCa metastasis in vitro.

The association of 14 single nucleotide polymorphisms (SNPs) of GPRC6A and linked to GPRC6A were evaluated with PCa risk and aggressive PCa in 916 subjects. Metastasis behavior was determined in GPRC6A knockdown PC3 cells, and the expressions of matrix metalloproteinase (MMP)2 and MMP9 were detected. Bone transcription factor runt-related transcription factor 2 (RUNX2) and epithelial-mesenchymal transition (EMT) marker genes were examined in the GPRC6A overexpression PC3 cells.

Among the 14 SNPs tested in PCa patients and controls, 4 were associated with aggressive PCa (p = 0.032-0.037, odds ratio = 1.38-1.41). Both the migration and invasion abilities were reduced in PC3 cells that were transiently transfected with GPRC6A short interfering RNA (siRNA). The GPRC6A knockdown cells showed reduced activity levels of MMP2 and MMP9. Furthermore, RUNX2, EMT and ERK signaling were shown to be up-regulated in GPRC6A overexpression cells.

These findings suggest that GPRC6A is associated with aggressive PCa. GPRC6A knockdown inhibits the PCa cells migration and invasion, and GPRC6A overexpression promotes the EMT. It is suggested that GPRC6A may serve as a potential therapeutic target for metastatic PCa.