Prognostic relevance of Tiam1 protein expression in prostate carcinomas

Abstract

The Rac-specific guanine nucleotide exchange factor, Tiam1, plays a major role in oncogenicity, tumour invasion and metastasis but its usefulness as a prognostic marker in human cancer has not been tested yet. In the present study, Tiam1 expression was analysed in benign secretory epithelium, pre-neoplastic high-grade prostatic intraepithelium neoplasia (HG-PIN) and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Tiam1 proved significantly overexpressed in both HG-PIN (Po0.001) and prostate carcinomas (Po0.001) when compared to benign secretory epithelium. Strong Tiam1 overexpression (i.e. X3.5-fold) in prostate carcinomas relative to the respective benign prostatic epithelium was statistically significantly associated with disease recurrence (P ¼ 0.016), the presence of lymph vessel invasion (P ¼ 0.031) and high Gleason scores (GS) (i.e. X7) (P ¼ 0.044). Univariate analysis showed a statistically significant association of strong Tiam1 overexpression with decreased disease-free survival (DFS) (P ¼ 0.03). This prognostic effect of strong Tiam1 overexpression remained significant in multivariate analysis including preoperative prostate-specific antigen levels, pT stage, and GS (relative risk ¼ 3.75, 95% confidence interval ¼ 1.06 -13.16; P ¼ 0.04). Together, our data suggest that strong Tiam1 overexpression relative to the corresponding benign epithelial cells is a new and independent predictor of decreased DFS for patients with prostate cancer.

Blockade of Rac1 Activity Induces G1 Cell Cycle Arrest or Apoptosis in Breast Cancer Cells through Downregulation of Cyclin D1, Survivin, and X-Linked Inhibitor of Apoptosis Protein

“…Repression of Rac1 activity by NSC23766 diminished Rac-dependent cell proliferation of PC3 prostate cancer line (36) and leukemia cell lines both in vitro and in vivo (37)(38)(39)(40); it also inhibited cell migration of several breast cancer cell lines (41) and induced apoptosis in leukemia (37)(38)(39)(40) and glioma (42) cell lines. Increasing evidence shows that Tiam1 and Trio are overexpressed in different types of human tumors (18)(19)(20), including human breast (42) carcinomas, which is believed to contribute to Rac1 hyperactivity. This promoted us to investigate whether targeting Rac1 could be beneficial in eliminating cancer cells.…”

“…For instance, NF-κB activation is known to induce transcription of its target genes such as cyclin D1, Bcl-2, and Bcl-XL. In human cancers, Rac1 is found to be frequently hyperactivated due to elevated protein expression in itself (16,17) or alteration in its regulatory proteins (18)(19)(20). The dysregulated Rac1 activity has been implicated in several aspects of malignant phenotypes such as tumorigenic transformation and outgrowth (21)(22)(23)(24)(25).…”

Clinical implication of Tiam1 overexpression in the prognosis of patients with serous ovarian carcinoma

“…Nevertheless, several reports have indicated that the high expression of Tiam1 is significantly associated with the shortened survival of patients with malignancies. For example, Engers et al reported that high Tiam1 expression is an independent predictor of decreased disease-free survival for patients with prostate cancer (16). Yang et al demonstrated that the high expression of Tiam1 correlates with a poor prognosis in hepatocellular carcinoma (29).…”

“…Tiam1 is a potent modifier of oncogenic Ras-induced skin tumor initiation, promotion and progression (13). Moreover, numerous studies have demonstrated that the upregulation of Tiam1 is associated with an aggressive phenotype and a poor clinical outcome in several types of malignant tumors, including breast (14), colon (15), prostate (16), liver (17) and nasopharyngeal (11) esophageal squamous cell carcinoma (18). However, to date, the correlation between Tiam1 expression and ovarian carcinoma has not been adequately investigated.…”

Expression of Tiam1 in Lung Cancer and its Clinical Significance

“…Tiam1 was first discovered in a proviral insertion mutation study, and isolated and identified in the highly aggressive mice T lymphoma cells variants, also called T-cell lymphoma invasion and metastasis-inducing factor 1 (Tiam1) (Fleming et al, 2000;Engers et al, 2006;Li et al, 2011;Chen et al, 2012). The chemical component protein serves as a guanylic acid transfer factor, which can transform the guanylic acid bisphosphate into guanylic acid triphosphoric acid and promote guanylic acid bisphosphate release and binding to guanylic acid triphosphoric acid.…”