G protein-coupled receptors (GPCRs) and their
ligands have been implicated in progression and
metastasis of several
cancers. GPCRs signal through
heterotrimeric G proteins, and among the different types of
G proteins, GNA12/13 have been most closely linked to
tumor progression. In this study, we explored the role of GNA13 in
prostate cancer cell invasion and the mechanism of up-regulation of GNA13 in these cells. An initial screen for GNA13
protein expression showed that GNA13 is highly expressed in the most aggressive
cancer cell lines. Knockdown of GNA13 in highly invasive PC3 cells revealed that these cells depend on GNA13 expression for their invasion, migration, and Rho activation. As
mRNA levels in these cells did not correlate with
protein levels, we assessed the potential involvement of micro-RNAs (
miRNAs) in post-transcriptional control of GNA13 expression. Expression analysis of
miRNAs predicted to bind the 3'-UTR of GNA13 revealed that miR-182 and miR-141/200a showed an inverse correlation to the
protein expression in LnCAP and PC3 cells. Ectopic expression of miR-182 and miR-141/200a in PC3 cells significantly reduced
protein levels, GNA13-3'-UTR reporter activity and in vitro invasion of these cells. This effect was blocked by restoration of GNA13 expression in these cells. Importantly, inhibition of miR-182 and miR-141/200a in LnCAP cells using specific
miRNA inhibitors elevated the expression of GNA13 and enhanced invasion of these cells. These data provide strong evidence that GNA13 is an important mediator of
prostate cancer cell invasion, and that miR-182 and miR-200 family members regulate its expression post-transcriptionally.