Abstract LB-278: MicroRNA control of GNA13 expression and cancer cell invasion

Heterotrimeric guanine nucleotide binding proteins (G proteins) transmit a variety of extracellular signals from cell surface G protein-coupled receptors (GPCRs) to intracellular effector molecules. Heterotrimeric G proteins are classified according to the α subunit into four subfamilies: Gs, Gi, Gq, and G12. The G12 subfamily, which is comprised of two members, Gα12 (GNA12) and Gα13 (GNA13), has been implicated in cancer cell invasion and metastasis. G12 signaling promotes prostate, breast and ovarian cancer cell invasion in vitro, and these proteins are highly expressed in metastatic cancer tissues. As part of a program to elucidate the mechanisms by which GNA12 and GNA13 expression is upregulated in cancer cells, we assessed the potential involvement of micro-RNAs (miRNAs) in post-transcriptional control of GNA13 expression. The initial focus was on prostate cancer; LnCAP (with the lowest GNA13 protein level) and PC3 (with the highest GNA13 level) were employed as the model system. 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 mRNA and protein levels, as well as GNA13 3′UTR- reporter activity. Further, expression of these miRNAs significantly inhibited PC3 cell invasion in an in vitro matrigel invasion assay, and this effect was blocked by overexpression of GNA13 in these cells. Importantly, inhibition of miR-182 and miR-141/200a in LnCAP cells using specific miRNA inhibitors (anti-miRs) elevated the expression of GNA13 and enhanced the basal invasion of these cells. These data provide strong evidence that GNA13 expression is regulated by post-transcriptional mechanisms involving miR-182 and miR-200 family members. Further studies are being performed to identify the role of these miRNAs in cancer progression and to determine the importance of impact on GNA13 expression as an important mediator of this effect. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-278. doi:1538-7445.AM2012-LB-278