Hainan Liu

SMYD3 as an Oncogenic Driver in Prostate Cancer by Stimulation of Androgen Receptor Transcription

BACKGROUND Androgen receptor (AR) is critical for prostate tumorigenesis and is frequently overexpressed during prostate cancer (PC) progression. However, few studies have addressed the epigenetic regulation of AR expression. METHODS We analyzed SMYD3 expression in human PC with Western blot and immunohistochemistry. SMYD3 expression was knocked down using short hairpin RNA (shRNA) or small interfering RNA (siRNA). Cell proliferation, colony formation, and apoptosis analyses and xenograft transplantation were performed to evaluate the impact of SMYD3 depletion on PC cells. AR expression and promoter activity were determined using real-time quantitative polymerase chain reaction, western blot, and luciferase reporter assay. AR promoter association with Sp1, SMYD3, and histone modifications was assessed by chromatin immunoprecipitation. Differences in AR mRNA abundance and promoter activity were analyzed using Wilcoxon signed-rank tests, SMYD3 expression was analyzed using with Mann-Whitney U tests for unpaired samples, and tumor weight was analyzed with Student t test. All statistical tests were two-sided. RESULTS The upregulation of SMYD3 protein expression was observed in seven of eight prostate tumor specimens, compared with matched normal tissues. Immunohistochemical analysis showed a strong SMYD3 staining in the nuclei of PC tissues in eight of 25 (32%) cases and in the cytoplasm in 23 out of 25 (92%) cases, whereas benign prostate tissue exhibited weak immunostaining. Depletion of SMYD3 by siRNA or shRNA inhibited PC cell proliferation (72 hours relative to 24 hours: control shRNA vs SMYD3 shRNA 1: mean fold change = 2.76 vs 1.68; difference = 1.08; 95% confidence interval = 0.78 to 1.38, P < .001), colony formation, cell migration, invasion, and xenograft tumor formation. Two functional SMYD3-binding motifs were identified in the AR promoter region. CONCLUSIONS SMYD3 promotes prostate tumorigenesis and mediates epigenetic upregulation of AR expression.

Association between HIF1A P582S and A588T Polymorphisms and the Risk of Urinary Cancers: A Meta-Analysis

Purpose The hypoxia-inducible factor-1 alpha (HIF1A) plays a vital role in cancer initiation and progression. Previous studies have reported the existence of HIF1A P582S and A588T missense polymorphisms in renal, urothelial and prostatic carcinomas, however the effects remain conflicting. Therefore, we performed a meta-analysis to assess the association between these sites and the susceptibility of urinary cancers. Methods We searched the PubMed database without limits on language until Nov 25, 2012 for studies exploring the relationship of HIF1A P582S and A588T polymorphisms and urinary cancers. Still, article search was supplemented by screening the references of retrieved studies manually. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the strength of the associations between the two by RevMan 5.0 software. Simultaneously, publication bias was estimated by funnel plot and Begg’s test with Stata 12.1 software. Results Overall, 11 individual case-control studies with 5195 cases and 5786 controls for P582S polymorphism, and 9 studies with 3482 cases and 4304 controls for A588T polymorphism were respectively included in the final meta-analysis. For HIF1A P582S polymorphism, individuals with TT genotype showed 1.60 fold higher risk than the others carrying CT or CC genotypes in Caucasian population (OR = 1.60, 95% CI = 1.09–2.33, P heterogeneity = 0.11, P = 0.02). For HIF1A A588T polymorphism, the A allele was significantly correlated with higher urinary cancers risk in Asian population (OR = 1.41, 95% CI = 1.03–1.93, P heterogeneity = 0.22, P = 0.03). Still, significant associations were found for prostate cancer in the allele and dominant models (OR = 1.46, 95% CI = 1.01–2.12, P heterogeneity = 0.49, P = 0.04 and OR = 1.45, 95% CI = 1.00–2.12, P heterogeneity = 0.50, P = 0.05). Conclusions The current findings suggest that HIF1A P582S polymorphism correlates with urinary cancers risk in Caucasian population, while A588T polymorphism may increase the risk of urinary cancers in Asian population and prostate cancer.

Overexpression of Reptin in renal cell carcinoma contributes to tumor malignancies and its inhibition triggers senescence of cancer cells

OBJECTIVES Reptin is an AAA+ ATPase associated with several complexes involved in chromatin remodeling, transcriptional regulation, DNA damage repair, and telomerase activity. Functional studies have implicated reptin in many cellular processes highly relevant to cancer. In this study, we investigated reptin expression in renal cell carcinoma (RCC) and its biologic functions in RCC cells. MATERIALS AND METHODS A total of 81 RCC patients were involved in the study. Cancerous and adjacent normal renal tissues were analyzed for reptin expression using immunohistochemistry. Univariate association with survival was evaluated using Kaplan-Meier curves. Gene expression was depleted with specific small interference RNA. Clonogenesis, cellular senescence, and cell cycle distribution were examined by foci formation, β-galactosidase staining, and flow cytometry, respectively. Cell migration and invasion capability were determined by scratch migration assay and Matrigel invasion assay. RESULTS Reptin is overexpressed in cancerous tissues compared with tumor adjacent renal tissues. Cytoplasmic expression of reptin positively correlates with the poor differentiation of RCC, and predicts an unfavorable outcome for patients. Depleting reptin expression substantially inhibited clonogenic potential of cancer cells and induced senescence of RCC cells. Moreover, reptin depletion attenuated migration and invasion ability of RCC cells in vitro. CONCLUSIONS Reptin is overexpressed and aberrantly distributed in RCC. It is required for sustained proliferation of cancer cells by preventing cell growth arrest and senescence. Furthermore, reptin promotes cell migration and invasion, which may contribute to the progression of RCC. Therefore, reptin may prove to be a valuable target for prevention and treatment of renal cell carcinoma.

Microvessel density and heparanase over-expression in clear cell renal cell cancer: correlations and prognostic significances

BackgroundTumor angiogenesis is important in the progression of malignancies, and heparanase plays an important role in sustaining the pathology of clear cell renal cell cancer (ccRCC). The study was carried out to investigate the correlations between microvessel density (MVD) and heparanase expression containing prognostic significances in the patients with ccRCC.MethodsSpecimens from 128 patients with ccRCC were investigated by immunohistochemistry for MVD. RT-PCR and immunohistochemistry were used to detect heparanase expression. Correlations between MVD, heparanase expression, and various clinico-pathological factors were studied. The prognostic significances of MVD and heparanase expression were also analysed.ResultsWe discovered a statistically significant prevalence of higher MVD in ccRCC compared with adjacent normal renal tissues. MVD was positively correlated with TNM stage and distant metastasis in ccRCC patients, and was also correlated with the expression level of heparanase.Heparanase is over-expressed and correlated with TNM stage, histologic grade, distant metastasis and lymphatic metastasis in ccRCC. High MVD and heparanase over-expression inversely correlate with the survival of ccRCC patients.ConclusionsHeparanase contributes to angiogenesis of ccRCC and over-expression of heparanase is an independent predictors of prognosis for ccRCC. MVD is correlated with tumor development and metastasis in ccRCC.

Lack of Association between hOGG1 Ser326Cys Polymorphism and the Risk of Bladder Cancer: A Meta-Analysis

Objective: In some but not all studies, hOGG1 Ser326Cys polymorphism has been reported to contribute to the risk of bladder cancer. To determine whether there is a significant association of hOGG1 Ser326Cys polymorphism with the susceptibility for bladder cancer, we performed a comprehensive meta-analysis. Methods: The electronic PubMed, Medline and Springer databases were searched for publications on the association between hOGG1 Ser326Cys polymorphism and bladder cancer through to May 20, 2011. Seven case-control studies were identified, including 2,474 cases and 2,408 controls. From these identified publications, crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association using fixed- or random-effects models. Two investigators each extracted data and conducted the analysis independently. Results: Overall, no significant associations were found between hOGG1 Ser326Cys polymorphism and bladder cancer in codominant models (GG vs. CC: OR 1.11, 95% CI 0.74–1.66, p = 0.63; GC vs. CC: OR 1.07, 95% CI 0.80–1.41, p = 0.65). Similarly, no significant associations with bladder cancer were observed in the recessive model (GG vs. GC+CC: OR 1.05, 95% CI 0.65–1.70, p = 0.85), dominant model (GG+GC vs. CC: OR 1.07, 95% CI 0.87–1.32, p = 0.53) and allele model (G vs. C: OR 1.06, 95% CI 0.90–1.26, p = 0.49). In the stratified analyses by ethnicity, control sources, pathology, Hardy-Weinberg equilibrium, significant associations were still not observed. Conclusions: The overall current literature on hOGG1 Ser326Cys polymorphism and the risk of bladder cancer suggests no statistically significant association between the two. Additional primary studies may be necessary to provide evidence of any significant association between this specific polymorphism and bladder cancer.

Downregulated expression of hepatoma-derived growth factor inhibits migration and invasion of prostate cancer cells by suppressing epithelial-mesenchymal transition and MMP2, MMP9

Hepatoma-derived growth factor (HDGF) is commonly over-expressed and plays critical roles in the development and progression in a variety of cancers. It has previously been shown that HDGF is overregulated in prostate cancer cells compared to normal prostate cells, which is correlated with cellular migration and invasion of prostate cancer. Here, the molecular mechanisms of HDGF in prostate cancer is investigated. It is shown that HDGF knockdown reduces prostate cancer cellular migration and invasion in both androgen-sensitive LNCaP cells and androgen-insensitive DU145 and PC3 cells. Furthermore, Western blot analysis reveals that HDGF knockdown inhibits epithelial-mesenchymal transition (EMT) of prostate cancer cells by upregulation of protein E-cadherin and downregulation of proteins N-cadherin, Vimentin, Snail and Slug. In addition, mechanistic studies reveal that proteins MMP2 and MMP9 are down-regulated. In conclusion, our data suggested that HDGF knockdown inhibits cellular migration and invasion in vitro of prostate cancer via modulating epithelial-mesenchymal transition (EMT) signaling pathway, as well as MMP2 and MMP9 signaling pathway. These results supported that HDGF is a relevant protein in the progression of prostate cancer and may serve as a potentially therapeutic target for prostate cancer as well as its downstream targets.

Serum Cystatin C Level Is Not a Promising Biomarker for Predicting Clinicopathological Characteristics of Bladder Urothelial Tumors

The role of cystatin C (Cys-C) in tumorigenesis and progression of bladder urothelial tumors (BUT) is still indefinite. We retrospectively collected the clinical information from the records of 425 BUT patients. Pretreatment serum Cys-C levels were compared across the various groups. Then we subgroup the patients with GFR ≥ 90 mg/min/1.73 m2, to exclude the effects of lower renal function on cystatin C. No statistically significant differences in the levels of serum Cys-C were found among the tumor characteristics (all P > 0.05). In conclusion, circulating Cys-C was not a reliable predictor for clinicopathological characteristics of BUT patients.

Pretreatment Serum Cystatin C Levels Predict Renal Function, but Not Tumor Characteristics, in Patients with Prostate Neoplasia

To evaluate the role of Cystatin C (Cys-C) in tumorigenesis and progression of prostate cancer (PCa), we retrospectively collected the clinical information from the records of 492 benign prostatic hyperplasia (BPH), 48 prostatic intraepithelial neoplasia (PIN), and 173 PCa patients, whose disease was newly diagnosed and histologically confirmed. Pretreatment serum Cys-C levels were compared across the various groups and then analyzed to identify relationships, if any, with clinical and pathological characteristics of the PCa patient group. There were no significant differences in serum Cys-C levels among the three groups (P > 0.05). In PCa patients with normal SCr levels, patient age was correlated with serum Cys-C level (P ≤ 0.001) but did not correlate with alkaline phosphatase (AKP), lactate dehydrogenase (LDH), prostate specific antigen (PSA), Gleason score, or bone metastasis status (P > 0.05). Age and SCr contributed in part to the variations in serum Cys-C levels of PCa patients (r = 0.356, P ≤ 0.001; r = 0.520, P ≤ 0.001). In conclusion, serum Cys-C levels predict renal function in patients with prostate neoplasia, but were not a biomarker for the development of prostate neoplasia, and were not correlated with the clinicopathological characteristics of PCa.