Prognostic relevance of increased Rac GTPase expression in prostate carcinomas

Abstract

Rac proteins of the Rho-like GTPase family, including the ubiquitous Rac1, the hematopoiesisspecific Rac2, and the least-characterized Rac3 play a major role in oncogenic transformation, tumor invasion and metastasis. However, the prognostic relevance of Rac expression in human tumors has not been investigated yet. In the present study, Rac protein expression was analyzed in benign secretory epithelium, high-grade prostatic intraepithelium neoplasia (HG-PIN), and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Thus, Rac proteins were significantly strongly expressed in HG-PIN (P!0.001) and prostate carcinomas (P!0.001) when compared with benign secretory epithelium. Accordingly, all tumor tissues analyzed by isoform-specific real-time PCR (nZ7) exhibited significantly higher RNA expression levels of Rac (i.e. sum of Rac1 and Rac3 expression levels) than the respective benign counterparts (PZ0.018) and this appeared to result mainly from increased expression of the Rac3 isoform as verified by immunoblotting. Univariate analyses showed statistically significant associations of increased Rac protein expression in prostate cancer (PZ0.045), preoperative prostate-specific antigen levels (PZ0.044), pT stage (PZ0.002), and Gleason score (PZ0.001) with decreased disease-free survival (DFS). This prognostic effect of increased protein expression of Rac remained significant even in a multivariate analysis including all these four factors (relative riskZ3.22, 95% confidence intervalZ1.04-10.00; PZ0.043). In conclusion, our data suggest that increased Rac protein expression in prostate cancer relative to the corresponding benign secretory epithelium is an independent predictor of decreased DFS and appears to result mainly from increased expression of the Rac3 isoform.

Silencing of Rac3 Inhibits Proliferation and Induces Apoptosis of Human Lung Cancer Cells

“…Also, inhibition of Rac1 expression or disruption of its function significantly reduced cancer cells metastasis in a multitude of tumor models (Chan et al, 2005;Niggli et al, 2009). R Engers et al suggested that increased Rac protein expression in prostate cancer was an independent predictor of decreased disease free survival (DFS) and appeared to result mainly from increased expression of the Rac3 isoform (Engers et al, 2007). However, the mechanism by which Rac3 increases the invasive potential remains to be determined.…”

“…Aberrant activation of Rac3 has been recognized to be crucial in tumor proliferation in both breast cancer and prostate cancer (Engers et al, 2007;Walker et al, 2011). Previous reports implicated that Rac3 may play a paramount role in cell proliferation and cytoskeletal organization (Mira et al, 2000;Chatterjee et al, 2011;Gest et al, 2013).…”

Vav3-Rac1 Signaling Regulates Prostate Cancer Metastasis with Elevated Vav3 Expression Correlating with Prostate Cancer Progression and Posttreatment Recurrence

“…Accumulating evidence indicates the important role of Rac1-mediated signaling in malignant transformation (35,36). Elevated expression of Rac1 in prostate cancer (37) and its suppression of the cyclin-dependent kinase inhibitor p21 (CIP1) in prostate cancer cells (38) suggest the involvement of Rac1 in prostate cancer progression. Several Rac-specific GEFs have been linked to tumor progression, such as Tiam1 (39) and DOCK3 (40).…”

Rab5 is required for Caveolin-1-enhanced Rac1 activation, migration and invasion of metastatic cancer cells

“…Interestingly, expression of all three proteins is known to be deregulated in cancer, and their overexpression is associated with poor patient prognosis (Engers et al, 2007;Liu et al, 2013;Meije et al, 2002;Yang et al, 1999;Yang et al, 2011). Moreover, this novel mechanism is dependent on the Rac1-GEF Tiam1, which is also known to be overexpressed in cancer (Chen et al, 2012;Zhao et al, 2011).…”