Ranlu Liu

Association between COX-2 rs2745557 polymorphism and prostate cancer risk: a systematic review and meta-analysis

BackgroundEvidence is accumulating that chronic inflammation may have an important role in prostate cancer (PCa). The COX-2 polymorphism rs2745557 (+202 C/T) has been extensively investigated as a potential risk factor for PCa, but the results have thus far been inconclusive. This meta-analysis was performed to derive a more precise estimation of the association.MethodsA comprehensive search was conducted to identify all case-control studies of COX-2 rs2745557 polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. Statistical analyses were performed by Review Manage, version 5.0 and Stata 10.0.ResultsA total of 8 available studies were considered in the present meta-analysis, with 11356 patients and 11641 controls for rs2745557. When all groups were pooled, there was no evidence that rs2745557 had significant association with PCa under co-dominant, recessive, over-dominant, and allelic models. However, our analysis suggested that rs2745557 was associated with a lower PCa risk under dominant model in overall population (OR = 0.85, 95%CI = 0.74-0.97, P = 0.02). When stratifying for race, there was a significant association between rs2745557 polymorphism and lower PCa risk in dominant model comparison in the subgroup of Caucasians (OR = 0.86, 95%CI = 0.75-0.99, P = 0.04), but not in co-dominant, recessive, over-dominant and allelic comparisons.ConclusionBased on our meta-analysis, COX-2 rs2745557 was associated with a lower PCa risk under dominant model in Caucasians.

Overexpressed MicroRNA-182 Promotes Proliferation and Invasion in Prostate Cancer PC-3 Cells by Down-Regulating N-myc Downstream Regulated Gene 1 (NDRG1)

MicroRNAs, non-coding 20–22 nucleotide single-stranded RNAs, result in translational repression or degradation and gene silencing of their target genes, and significantly contribute to the regulation of gene expression. In the current study, we report that miR-182 expression was significantly upregulated in prostate cancer tissues and four cell lines, compared to benign prostatic hyperplasia tissues and normal prostatic epithelial (RWPE-1) cells. Ectopic overexpression of miR-182 significantly promotes the proliferation, increases the invasion, promotes the G1/S cell cycle transition and reduces early apotosis of PC-3 cells, while suppression of miR-182 decreased the proliferation and invasion, inhibits the G1/S cell cycle transition and increase early apotosis of PC-3 cells. Additionally, we demonstrated that miR-182 could downregulate expression of NDRG1 by directly targeting the NDRG1 3′-untranslated region. In conclusion, our results suggest that miR-182 plays an important role in the proliferation of human prostate cancer cells by directly suppressing the tumor supressor gene NDRG1. We uncovered a new epigenetic regulation of NDRG1.

Vasculogenic mimicry is a marker of poor prognosis in prostate cancer.

We investigated the role of vasculogenic mimicry (VM) in the progression of prostate cancer (PCa). Ninety-six patients who had undergone prostatectomy for treatment of PCa and for whom a complete record of clinical and follow-up data were available were reviewed. VM and matrix metalloproteinase-2 (MMP-2) were detected by immunohistochemical staining in frozen tissue sections. Relationship between VM and clinicopathological variables was analyzed statistically. Multivariate analyses were performed to assess the prognostic significance of VM. Results showed that out of the 96 PCa cases studied here, VM was detectable in 24 (25%) and was positively correlated with preoperative prostate-specific antigen (PSA) level, Gleason score, pathological stage, lymph node metastasis, seminal vesicle invasion, distant metastasis and PSA doubling time (PSADT). Univariate analysis showed that VM, PSA level, Gleason score, distant metastasis and PSADT were correlated with overall survival (OS), while VM, Gleason score, distant metastasis, local recurrence and PSADT were correlated with disease-free survival (DFS). Multivariable analysis indicated that the presence of VM, higher Gleason score and distant metastasis were the adverse predictors of OS and DFS. A higher widespread staining for MMP-2 was correlated with the VM-positive subgroup. In conclusion, VM mainly exists in the high risk PCa patients and is an independent marker of poor prognosis.

Overexpression of LAPTM4B-35: A Novel Marker of Poor Prognosis of Prostate Cancer

Background Lysosome-associated protein transmembrane 4b-35 (LAPTM4B-35) is a member of the mammalian 4-tetratransmembrane spanning protein superfamily, which is overexpressed in several solid malignancies. However, the expression of LAPTM4B-35 and its role in the progression of prostate cancer (PCa) is unknown. The aim of the present study was to investigate the LAPTM4B-35 expression in PCa and its potential relevance to clinicopathological variables and prognosis. Methods Immunohistochemistry was used to determine the expression of LAPTM4B-35 protein in 180 PCa tissues in comparison with 180 normal benign prostatic hyperplasia (BPH) specimens. The correlation between the expression of the LAPTM4B-35 protein and the clinicopathologic characteristics of patients with PCa was analyzed. Results Statistical analysis showed that LAPTM4B-35 expression was significantly elevated in PCa compared with the BPH controls. High LAPTM4B-35 staining was present in 71.11% of all the cases with PCa. The overexpression of LAPTM4B-35 was significantly associated with the lymph node metastasis, seminal vesicle invasion, PCa stage, higher Gleason score, higher preoperative PSA, and biochemical recurrence (BCR). The Kaplan-Meier survival analysis showed that the high expression of LAPTM4B-35 was related to the poor overall survival and BCR-free survival of patients with PCa. Multivariate Cox analysis showed that LAPTM4B-35 was an independent prognostic factor for both overall survival and BCR-free survival of patients with PCa. Conclusions Overexpression of LAPTM4B-35 may be associated with tumor progression and poor prognosis in PCa and thus may serve as a new molecular marker to predict the prognosis of PCa patients.

The Interleukin-6 –174G/C Polymorphism and Prostate Cancer Risk: A Systematic Review and Meta-Analysis

Objective: This systematic review and meta-analysis was undertaken to integrate previous findings and summarize the effect size of the association of interleukin-6 (IL-6) genetic polymorphism –174G/C with susceptibility to prostate cancer (PCa). Methods: All eligible studies of IL-6 –174G/C polymorphism and PCa risk were collected from the following electronic databases: PubMed and the Cochrane Library, with the last report up to June 1, 2011. Statistical analyses were performed by Review Manage version 5.0 and Stata 10.0. Results: A total of 7 independent studies, including 9,959 cases and 12,361 controls, were identified. When all studies were pooled, we did not detect a significant association of –174G/C polymorphism with PCa risk. When stratifying for race, similar results were obtained; evidence of a significant relation was absent in both Caucasians and the mixed population. After stratifying the studies by study types, –174G/C polymorphism was significantly associated with PCa risk when examining the contrast of CC + GC versus GG (OR = 1.44, 95% CI = 1.05–1.98, p = 0.03) in cohort studies but not in case-control studies. Conclusions: Our review suggest that –174G/C polymorphism is associated with an increased PCa risk in two cohort studies from one article. Additional well-designed studies are warranted to validate these findings.

Double-targeted and double-enhanced suicide gene therapy mediated by generation 5 polyamidoamine dendrimers for prostate cancer.

Herpes simplex virus (HSV)‐thymidine kinase (TK)/ganciclovir (GCV) system is one of the most widely used and efficient suicide gene therapy for prostate cancer, but the lack of favorable gene vector and target limits its application. In this study, we established a novel system using nonviral gene vector G5‐PAMAM‐D to express HSV‐TK and connexin43 (Cx43) gene driven by prostate‐specific membrane antigen (PSMA) promoter, and evaluated the anti‐tumor effect of this system. G5‐PAMAM‐D delivered PSMAe/p‐TK‐Cx43 showed expression of TK and Cx43 only in LNCaP cells, but not in PC‐3 and other cells. The transfection efficiency of this system was comparable to lipofectamine 2000 by propidium iodide staining assay. With gemcitabine, folate‐G5‐PAMAM‐D delivered PSMAe/p‐TK‐Cx43 (folate‐G5‐PAMAM‐D/PSMAe/p‐TK‐Cx43) significantly decreased prostate cancer LNCaP cell proliferation and promoted apoptosis in vitro. With gemcitabine, the systemic deliver of folate‐G5‐PAMAM‐D/PSMAe/p‐TK‐Cx43 significantly inhibited tumor growth in the LNCaP xenograft animal model. Our study demonstrates that this double‐targeted and double‐enhanced system is effective in inducing cell growth inhibition and apoptosis in vitro and suppressing tumor growth in vivo. In conclusion, Cx43 and gemcitabine combined with HSV‐TK/GCV gene therapy using nonviral vector G5‐PAMAM‐D hold great potential as a novel approach for the gene therapy of prostate cancer.

Tissue-selective RNA interference in prostate cancer cell using prostate specific membrane antigen promoter/enhancer

OBJECTIVES RNA interference (RNAi) has the potential to be developed into therapeutics for prostate cancer, but the lack of cellular targets limits its application. In the present study we attempt to develop a prostate cancer-specific RNAi system using the human prostate specific membrane antigen (PSMA) promoter/enhancer; furthermore, we analyzed its inhibitive effect on STAT3 expression. METHODS The adenoviral vectors containing a small hairpin RNA (shRNA) to target exogenous reporters enhance green fluorescent protein (EGFP) and endogenous gene signal transducers and activators of transcription 3 (STAT3) were constructed. After prostate cancer and other cells were transfected, reverse transcription-polymerase chain reaction (RT-PCR), fluorescence microscopy, and Western blotting were used to measure EGFP expression. Inhibition of STAT3 was evaluated by Western blotting. Cell proliferation and viability were measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Cell apoptosis was analyzed with double-staining of Annexin V and PI. RESULTS Our study showed that with the PSMA promoter/enhancer directly driving shRNA transcription, expression of the exogenous reporters EGFP in prostate cancer cells, but not other cancer cells and normal cells, was specifically inhibited in vitro. The PSMA promoter/enhancer-driven shRNA also depressed the expression of STAT3 in only prostate cancer cells. Inhibition of STAT3 suppressed proliferation of PC-3 and LNCaP cells. CONCLUSIONS The present study describes an efficient RNAi system for gene silencing that is specific to prostate cancer cells using the PSMA promoter/enhancer. Suppression of STAT3 by using this system decreased proliferation and induced apoptosis of PC-3 and LNCaP cells. This system may be useful for RNAi therapy for prostate cancer.

Expression of RABEX-5 and its clinical significance in prostate cancer

BackgroundWhile recent research has shown that expression of RABEX-5 in breast cancer and colorectal cancer has a crucial impact on tumor development, there is little information regarding RABEX-5 expression in prostate cancer. This study investigated the expression of RABEX-5 in prostate cancer by real time quantitative polymerase chain reaction and evaluated its association with clinicopathological variables, including prostate cancer patient prognosis.MethodsA total of 180 patients with primary prostate cancer treated by radical prostatectomy were enrolled. Real time quantitative polymerase chain reaction was utilized to investigate mRNA expression level of RABEX-5 in 180 paired prostate cancer/adjacent non-cancerous tissues. RABEX-5 mRNA expression was divided into high expression group and low expression group and correlations between RABEX-5 mRNA and clinicopathological factors were then evaluated. Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the association between RABEX-5 mRNA expression and prognosis of patients with prostate cancer.ResultsOur study showed that RABEX-5 mRNA was significantly upregulated in prostate cancer tissues. The data indicated that high expression of RABEX-5 mRNA was significantly associated with lymph node metastasis (P = 0.001), clinical stage (P = 0.004), biochemical recurrence (P = 0.009), preoperative prostate-specific antigen (P < 0.001), and Gleason score (P < 0.001). High RABEX-5 mRNA expression was a significant predictor of poor biochemical recurrence free survival and overall survival both in univariate and multivariate analysis.ConclusionThis is to our knowledge the first report investigating tumor RABEX-5 mRNA expression level in prostate cancer. We have shown that high RABEX-5 mRNA expression is a strong predictor of poor prognosis in prostate cancer patients treated by radical prostatectomy, and multivariate analysis confirmed RABEX-5 mRNA as an independent prognostic factor.

Downregulation of Nucleostemin Causes G1 Cell Cycle Arrest via a p53-Independent Pathway in Prostate Cancer PC-3 Cells

Aims: To screen the genes and possible signal transduction pathways with which nucleostemin (NS) interacts and explore the mechanism of NS in prostate cancer. Methods: NS-specific short-hairpin RNA expression plasmid was used to downregulate the NS level in PC-3 cells and the changes of cell cycle were studied. After that, oligonucleotide DNA microarray was used to screen the genome changes in PC-3 cells and quantitative real-time PCR was used to further confirm the differentially expressed genes. Results: Detection of cell cycle showed a decrease of S stage and an increase of G1 stage after downregulation of NS. 219 differentially expressed genes were found and these genes were involved in cell cycle, cell proliferation, signal transduction, cell apoptosis and cell differentiation, and so on. Genes related to cell cycle were discussed emphatically. INK4 family genes (P15, P16, P18) were upregulated while cyclin D1 HDAC1 were downregulated. These genes were tightly related to CDK4/6-cyclin D and pRb-E2F1 complexes. Conclusion: NS is an important G1/S checkpoint regulator and it could regulate cell cycles via a p53-independent pathway in prostate cancer.

Elf5 inhibits TGF-β-driven epithelial-mesenchymal transition in prostate cancer by repressing SMAD3 activation

The epithelial‐mesenchymal transition (EMT) has been associated with the acquisition of migration, invasiveness, and metastasis traits. During tumor progression, EMT can be induced by transforming growth factor‐β (TGF‐β) signal that epithelial cells receive from their microenvironment. However, the master regulatory controls on TGF‐β‐EMT axis are not understood.