Abstract
Regulator of G protein signaling 11 (RGS11), a member of the R7 subfamily of RGS proteins, is a well-characterized GTPase-accelerating protein that is involved in the heterotrimeric G protein regulation of the amplitude and kinetics of receptor-promoted signaling in retinal bipolar and nerve cells. However, the role of RGS11 in cancer is completely unclear. Using subtractive hybridization analysis, we found that RGS11 was highly expressed in the lymph-node metastatic tissues and bone-metastatic tumors obtained from patients with lung adenocarcinoma. Characterization of the clinicopathological features of 91 patients showed that around 57.1% of the tumor samples displayed RGS11 overexpression that was associated with primary tumor status, nodal metastasis and increased disease stages. Its high expression was an independent predictive factor for poor prognosis of these patients. Cotransfection of guanine nucleotide-binding protein beta-5 (GNB5) markedly increased RGS11 expression. Enhancement or attenuation of RGS11 expression pinpointed its specific role in cell migration, but not in cell invasion and proliferation. Signaling events initiated by the RGS11–GNB5 coexpression activated the c-Raf/ERK/FAK-mediated pathway through upregulation of the Rac1 activity. Consistently, increasing the cell invasiveness of the transfectants by additional cotransfection of the exogenous urokinase–plasminogen activator gene caused a significant promotion in cell invasion in vitro and in vivo, confirming that RGS11 functions in cell migration, but requires additional proteolytic activity for cell and tissue invasion. Collectively, overexpression of RGS11 promotes cell migration, participates in tumor metastasis, and correlates the clinicopathological conditions of patients with lung adenocarcinoma.
Highlights
In the past few decades, studies have shown that G protein-coupled receptors (GPCRs) are highly expressed in cancerous tissues and that their mitogenic ligands are enriched in metastatic sites [1, 2]
We found that Regulator of G protein signaling 11 (RGS11) was highly expressed in the lymph-node metastatic tissues and bonemetastatic tumors obtained from patients with lung adenocarcinoma
Using subtractive hybridization analysis of two pairs of primary lung adenocarcinoma and their metastatic tumor counterparts in lymph nodes (LNs), we found that RGS11 was highly overexpressed in lung metastatic adenocarcinoma, and its overexpression was associated with poorer prognosis, as reflected in shorter diseasefree and metastasis-free survivals
Summary
In the past few decades, studies have shown that G protein-coupled receptors (GPCRs) are highly expressed in cancerous tissues and that their mitogenic ligands are enriched in metastatic sites [1, 2]. The downstream signaling pathways include activation of phospholipase C, Src, and/or phosphatidylinositol 3 kinase [1, 3]. Regulation of the oncogenic GPCR activities and their downstream signaling is a critical issue for a better understanding of the molecular basis of cancer and for further developments in the diagnosis and treatment of cancer. The regulator of G protein signaling (RGS) family proteins function as guanosine triphosphatase (GTPase)accelerating proteins (GAP) that terminate Gα-coupled GPCR signaling rapidly through stabilization of the transition state during the hydrolysis of GTP by Gα [4]. RGS comprises diverse protein families whose members each have a unique tissue distribution, which is strongly related to signal transduction events. Many RGS proteins contain multiple structural and functional motifs through which they mediate crosstalk between GPCR-dependent and -independent signaling pathways. Aberrant G protein activation has been linked to the initiation and progression of various cancers [2, 5], the role of RGS proteins in tumor metastasis remains obscure
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