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Expression of FGD4 positively correlates with the aggressive phenotype of prostate cancer.

ABSTRACT: BACKGROUND:FGD4 (Frabin) is an F-actin binding protein with GTP/GDP exchange activity specific for CDC42. It is involved in reorganization of the actin cytoskeleton, which requires both actin binding and CDC42 activating function of FGD4. Expression of FGD4 is altered in patients with heterogeneous hereditary motor and sensory neuropathies as a result of demyelination of peripheral nerves. METHODS:In this study, we examined the expression of FGD4 in prostate cancer specimens using immunohistochemistry and studied the function of FGD4 in maintaining cell phenotype, behavior and drug sensitivity using overexpression and siRNA-based silencing approaches. We used Mann-Whitney test for comparative analysis of FGD4 expression. RESULTS:Our results show that the expression of FGD4 is upregulated in cancerous prostates compared to the luminal cells in benign prostatic hyperplasia, although the basal cells showed high staining intensities. We noted a gradual increase in the staining intensity of FGD4 with increasing aggressiveness of the disease. Inhibition of expression of FGD4 using siRNAs showed reduced proliferation and cell cycle arrest in G2/M phase of androgen dependent LNCaP-104S and androgen refractory PC-3 cells. Inhibition of FGD4 also resulted in reduced cell migration and CDC42 activities in PC-3 cells whereas, ectopic expression of FGD4 induced cell migration, altered expression of mesenchymal and epithelial markers and activation of CDC42/PAK signaling pathway. Reduced expression of FGD4 improved sensitivity of LNCaP-104S cells to the anti-androgen drug Casodex and PC-3 cells to the microtubule stabilizing drug docetaxel. CONCLUSIONS:Our data demonstrate a tumor promoting and a cell migratory function of FGD4 in prostate cancer cells and that inhibition of FGD4 expression enhances the response for both androgen-dependent and independent prostate cancer cells towards currently used prostate cancer drugs.

SUBMITTER: Bossan A

PROVIDER: S-EPMC6296060 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Expression of FGD4 positively correlates with the aggressive phenotype of prostate cancer.

Bossan Alexia A Ottman Richard R Andl Thomas T Hasan Md Faqrul MF Mahajan Nupam N Coppola Domenico D Chakrabarti Ratna R

BMC cancer 20181217 1

<h4>Background</h4>FGD4 (Frabin) is an F-actin binding protein with GTP/GDP exchange activity specific for CDC42. It is involved in reorganization of the actin cytoskeleton, which requires both actin binding and CDC42 activating function of FGD4. Expression of FGD4 is altered in patients with heterogeneous hereditary motor and sensory neuropathies as a result of demyelination of peripheral nerves.<h4>Methods</h4>In this study, we examined the expression of FGD4 in prostate cancer specimens using ...[more]

PMID: 30558664

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Project description:DNA methyltransferase (DNMT) is one of the major factors mediating the methylation of cancer related genes such as TGF-? receptors (T?Rs). This in turn may result in a loss of sensitivity to physiologic levels of TGF-? in aggressive prostate cancer (CaP). The specific mechanisms of DNMT's role in CaP remain undetermined. In this study, we describe the mechanism of TGF-?-mediated DNMT in CaP and its association with clinical outcomes following radical prostatectomy.We used human CaP cell lines with varying degrees of invasive capability to describe how TGF-? mediates the expression of DNMT in CaP, and its effects on methylation status of TGF-? receptors and the invasive capability of CaP in vitro and in vivo. Furthermore, we determined the association between DNMT expression and clinical outcome after radical prostatectomy. We found that more aggressive CaP cells had significantly higher TGF-? levels, increased expression of DNMT, but reduced T?Rs when compared to benign prostate cells and less aggressive prostate cancer cells. Blockade of TGF-? signaling or ERK activation (p-ERK) was associated with a dramatic decrease in the expression of DNMT, which results in a coincident increase in the expression of T?Rs. Blockade of either TGF-? signaling or DNMT dramatically decreased the invasive capabilities of CaP. Inhibition of TGF-? in an TRAMP-C2 CaP model in C57BL/6 mice using 1D11 was associated with downregulation of DNMTs and p-ERK and impairment in tumor growth. Finally, independent of Gleason grade, increased DNMT1 expression was associated with biochemical recurrence following surgical treatment for prostate cancer.Our findings demonstrate that CaP derived TGF-? may induce the expression of DNMTs in CaP which is associated with methylation of its receptors and the aggressive potential of CaP. In addition, DNMTs is an independent predictor for disease recurrence after prostatectomy, and may have clinical implications for CaP prognostication and therapy.

Project description:BACKGROUND: This study was undertaken to investigate the expression of guanyl nucleotide-releasing protein for Ras 3 (RasGRP3) in the cell lines and tissues in BPH and prostate cancer (PCa), as well as its associations with cancer invasion and prognosis in prostate carcinomas. METHODS: Expression analysis of RasGRP3 was accomplished using immunohistochemical staining of PCa and BPH tissues. Pearson's ?2 test was used to analyze the association between RasGRP3 expression and specific clinical parameters. Survival and PSA relapse curves were evaluated using the Kaplan-Meier curves and log-rank tests, and the differences were assessed using the Cox regression methods. In addition, human PCa cell lines PC-3, DU145, LNCaP, PC3M-1E8, PC3M-2B4 and BPH-1 were examined for expression of RasGRP3 using western blot and quantitative polymerase chain reaction (Q-PCR) analysis. After PC-3 cells were transfected by small interfering RNA targeting RasGRP3, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and migratory assays were employed to determine the vitality and aggressive capability of tumor cell in vitro. RESULTS: Expression of RasGRP3 was significantly correlated (P=0.038 and P=0.021) with Gleason score (< or =6 versus > or =7) and T stage (T1-T2 versus T3-T4), respectively. PCa with RasGRP3-positive expression may increase the risk of PSA recurrence and decrease cancer-specific survival (P=0.0291 and P=0.0044). The expression of RasGRP3 was also associated with PSA recurrence and cancer-specific survival in univariate (P<0.001 and P<0.001) and multivariate analyses (P<0.001 and P=0.003). RasGRP3 mRNA and proteins were found to be positively expressed in PCa cell lines. There was higher expression of RasGRP3 in PC-3, DU145 and PC3M-1E8 than in LNCaP, PC3M-2B4 and BPH-1. Knockdown of RasGRP3 inhibited the proliferation, migration and invasion capabilities of PC-3 cells. CONCLUSIONS: These data suggested that elevated RasGRP3 expression may play a key role in the malignant progression of PCa, especially in invasion and metastasis, and may be a potential marker of biochemical recurrence.

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Expression of FGD4 positively correlates with the aggressive phenotype of prostate cancer.

Publications

Expression of FGD4 positively correlates with the aggressive phenotype of prostate cancer.

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