GIT1 promotes lung cancer cell metastasis through modulating Rac1/Cdc42 activity and is associated with poor prognosis

Abstract

G-protein-coupled receptor kinase interacting protein 1 (GIT1) is participated in cell movement activation, which is a fundamental process during tissue development and cancer progression. GIT1/PIX forming a functional protein complex that contributes to Rac1/Cdc42 activation, resulting in increasing cell mobility. Although the importance of Rac1/Cdc42 activation is well documented in cancer aggressiveness, the clinical importance of GIT1 remains largely unknown. Here, we investigated the clinical significance of GIT1 expression in non-small-cell lung cancer (NSCLC) and also verified the importance of GIT1-Rac1/Cdc42 axis in stimulating NSCLC cell mobility. The result indicated higher GIT1 expression patients had significantly poorer prognoses in disease-free survival (DFS) and overall survival (OS) compared with lower GIT1 expression patients. Higher GIT1 expression was an independent prognostic factor by multivariate analysis and associated with migration/invasion of NSCLC cells in transwell assay. In vivo studies indicated that GIT1 promotes metastasis of NSCLC cells. Finally, GIT1 was found to stimulate migration/invasion by altering the activity of Rac1/Cdc42 in NSCLC cells. Together, the GIT1 expression is associated with poor prognosis in patients with NSCLC. GIT1 is critical for the invasiveness of NSCLC cells through stimulating the activity of Rac1/Cdc42.

The Long Intergenic Noncoding RNA 00707 Promotes Lung Adenocarcinoma Cell Proliferation and Migration by Regulating Cdc42

“…Recent studies show that deregulation of Cdc42 is involved in the activation of many cellular cascades such as cell polarity, cytoskeleton remolding, proliferation, migration, adhesion membrane trafficking, and transportation, and leads to the development of many pathological disorders including cancers in humans [26-28]. Stimulation of the G-protein-coupled receptor kinase interacting protein 1 (GIT1)-Rac/Cdc42 axis is important for cell motility in NSCLC, and thus activating of Rac1/Cdc42 is critical for the GIT1-induced invasiveness of NSCLC [29]. Proliferation of lung cancer cells was suppressed by upregulation of miR-137 both in vivo and in vitro by regulating the expression of Cdc42 and Cdk6 to some extent [30].…”

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

“…Searches for biomarkers for various tumors have identified both GIT and PIX. GIT1 is elevated in cervical cancer cell lines (Yoo et al, 2012), liver and colon cancer (Peng et al, 2013;Chen et al, 2015), melanoma (Huang et al, 2013), non-small cell lung cancer (Chang et al, 2015) and clear cell renal cancer , whereas GIT2 is downregulated in breast cancer (Sirirattanakul et al, 2015). α-PIX is overexpressed in glioma (Yokota et al, 2006) and downregulated in melanoma following TNFα treatment (de Lima et al, 2013).…”

Proteomic analysis reveals GIT1 as a novel mTOR complex component critical for mediating astrocyte survival

“…GIT1 can also act as a GTPase-activating protein for the ADP ribosylation factor family of small GTPases (Claing et al 2000;Vitale et al 2000), including Rac1 (Zhang et al 2005;Chang et al 2015), by binding to the C-terminal region of the Rho guanine nucleotide exchange factor 7 (ARHGEF7 or β-PIX) and promoting the interaction of β-PIX with Rac1 (Bagrodia et al 1999;Zhang et al 2005;Fiuza et al 2013). However, we observed no reproducible changes in Rac1 activity following shGit1 knockdown (Supplemental Fig.…”