Guanxiong Ding

Diabetes mellitus and prostate cancer risk of different grade or stage: A systematic review and meta-analysis

AIM Prior studies have reported that diabetes mellitus might reduce the overall prostate cancer risk. We examined this association by conducting a detailed meta-analysis of the studies published in peer-reviewed literature on the association between diabetes mellitus and prostate cancer risk of different stage or grade. METHODS A comprehensive search for articles of MEDLINE and EMBASE databases and bibliographies of retrieved articles published up to October 23, 2012 was performed. Methodological quality assessment of the trials was based on the Newcastle-Ottawa Scale. Meta-analysis was performed using STATA 12.0. RESULTS We included 9 studies in the meta-analysis (5 studies examining the relation of different stage only, 2 studies for grade only, and 2 studies for both grade and stage), and found an inverse association between diabetes mellitus and prostate cancer of different stage or grade. The relative risk (RRs) was moderately stronger for low grade (RR 0.74, 95% confidence interval (CI), 0.64-0.86) and localized disease (RR 0.72, 95% CI 0.67-0.76) compared with high grade (RR 0.78, 95% CI 0.67-0.90) and advanced disease (RR 0.85, 95% CI 0.75-0.97). CONCLUSION This study suggests an inverse relationship between diabetes mellitus and prostate cancer of different stage or grade. Possible biases underlying this association are discussed.

Over‐expression of lipocalin 2 promotes cell migration and invasion through activating ERK signaling to increase SLUG expression in prostate cancer

Metastasis is the primary cause of prostate cancer (PCa) lethality and poses a huge clinical obstacle. Lipocalin 2 (LCN2), a member of the lipocalin family, is aberrantly expressed in some human cancers and has been implicated in the progression of some tumors. However, the role of LCN2 in the metastatic capacity of prostate cancer (PCa) is poorly understood.

Med19 promotes bone metastasis and invasiveness of bladder urothelial carcinoma via bone morphogenetic protein 2.

Bladder cancer (BCa) remained a major health problem. Med19 was related to tumor growth of BCa. Bone morphogenetic proteins (BMPs) were reported to be critical in bone metastasis of cancer. We therefore investigated the relations between Med19 and BMPs in BCa and their effect on bone metastasis of BCa. Bladder cancer cell lines were cultured and interfered with Med19 shRNA and control. Expressions of BMP-1, BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-9, and BMP-15 were studied between 2 groups. Fifty-two BCa samples were included for immunohistochemical staining of Med19 and BMP-2. Expressions were scored and studied statistically. Invasiveness was studied with Transwell assay. Silencing or Med19 in BCa cells induced altered expressions of BMPs. Increased expressions of BMP-1, BMP-4, BMP-6, BMP-7, and BMP-15 and decreased expressions of BMP-2, BMP-5, and BMP-9 were noticed, but only BMP-2 reached statistical significance. Expressions of Med19 and BMP-2 were significantly higher in cases with bone metastasis and were positively correlated in cases with bone metastasis and muscle invasion. Med19 is a critical factor involved in the invasiveness and promotion of bone metastasis of BCa, possibly via BMP-2.

Combination of Rapamycin, CI-1040, and 17-AAG Inhibits Metastatic Capacity of Prostate Cancer via Slug Inhibition

Though prostate cancer (PCa) has slow progression, the hormone refractory (HRCP) and metastatic entities are substantially lethal and lack effective treatments. Transcription factor Slug is critical in regulating metastases of various tumors including PCa. Here we studied targeted therapy against Slug using combination of 3 drugs targeting 3 pathways respectively converging via Slug and further regulating PCa metastasis. Using in vitro assays we confirmed that Slug up-regulation incurred inhibition of E-cadherin that was anti-metastatic, and inhibited Bim-regulated cell apoptosis in PCa. Upstream PTEN/Akt, mTOR, Erk, and AR/Hsp90 pathways were responsible for Slug up-regulation and each of these could be targeted by rapamycin, CI-1040, and 17-AAG respectively. In 4 PCa cell lines with different traits in terms of PTEN loss and androgen sensitivity we tested the efficacy of mono- and combined therapy with the drugs. We found that metastatic capacity of the cells was maximally inhibited only when all 3 drugs were combined, due to the crosstalk between the pathways. 17-AAG decreases Slug expression via blockade of HSP90-dependent AR stability. Combination of rapamycin and CI-1040 diminishes invasiveness more potently in PCa cells that are androgen insensitive and with PTEN loss. Slug inhibited Bim-mediated apoptosis that could be rescued by mTOR/Erk/HSP90 inhibitors. Using mouse models for circulating PCa DNA quantification, we found that combination of mTOR/Erk/HSP90 inhibitors reduced circulating PCa cells in vivo significantly more potently than combination of 2 or monotherapy. Conclusively, combination of mTOR/Erk/Hsp90 inhibits metastatic capacity of prostate cancer via Slug inhibition.

PI3Kβ Inhibitor TGX221 Selectively Inhibits Renal Cell Carcinoma Cells with Both VHL and SETD2 mutations and Links Multiple Pathways

We aimed to exploit novel compounds with high selectivity to clear cell renal cell carcinoma (ccRCC) with common mutations. Using the GDSC databases, we searched for compounds with high selectivity for ccRCC with VHL and/or SETD2 mutations. Clinical impact and gene interactions were analysed using TCGA database. In vitro and in vivo studies were performed to validate the inhibitory effects of the compound. We identified the selective PI3Kβ inhibitor TGX221 as a selective inhibitor for ccRCC with both VHL and SETD2 mutations. TGX221 also targeted cancer cells with CDKN2A and PTEN mutations. Changes in PTEN and CDKN2A gene sets were associated with worsened prognosis of ccRCC. TGX221 substantially and selectively inhibited the down stream products of VHL, SETD2, and PTEN in ccRCC cells with VHL and SETD2 mutations. TGX221 also exhibited significant selectivity in inhibiting cell motility and tumourigenesis of ccRCC cells with VHL and SETD2 mutations. TGX221 is a novel inhibitor with high selectivity for ccRCC with VHL and SETD2 mutations. It also targeted PTEN and CDKN2A mutations. How those genes were associated with PI3Kβ warranted further investigations.

Predictive Value of Clinicopathological Markers for the Metachronous Bladder Cancer and Prognosis of Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma (UTUC) is rare but aggressive with poor prognosis. We aimed to find effective predictive markers for recurrence and prognosis in UTUC patients. In this retrospective study, we included 88 UTUC patients treated with radical neprhoureterectomy (RNU) and analyzed their clinicopathological parameters. For study of incidence of metachronous bladder tumor, models were adjusted with inclusion of prophylactic intravesical instillation chemotherapy. The mean follow-up was 28.59 months (2 to 82 mo). Lack of gross hematuria (RR 0.060, 95%CI 0.008–0.468), tumor located at ureter (RR 0.037, 95%CI 0.004–0.378), advanced stage and higher p53 expression were independent factors for worse survival. Recurrence of bladder cancer occurred 20% of patients at median follow-up of 37.65 months (5 to 82 mo). Higher tumor grade (RR 5.998, 95%CI 1.359–26.479) and presence of ipsilateral non-functioning kidney at diagnosis (RR 5.982, 95%CI 1.338–26.750) were predictors for recurrence. The present study identified several parameters with predictive value in the prognosis and intravesicle recurrence in UTUCand shed light on the better monitoring and management of the disease.

Ki67 and TP53 expressions predict recurrence of non-muscle-invasive bladder cancer

Tumor markers Ki67, TP53, and TP63 are common labels in the diagnosis of bladder cancer (BCa) around the world. The combination of those biomarkers may have advantages in predicting BCa prognosis and non-muscle-invasive bladder cancer (NMIBC) postoperative recurrence. We investigated the immunohistochemical profiles of 313 bladder cancer samples classified under the WHO/ISUP (2004) grading scale and the UICC-TNM (2002) classification. Then we investigated their predictive value in the tumor recurrence of 270 NMIBC patients after TURBT. Expression of Ki67 correlates with grade, stage, tumor size, and tumor numbers. Semiquantitative evaluation of TP53 correlates with grade and invasive conditions. The positive expression rate of TP63 correlated with tumor grade and stage. The combined effect of TP53 and Ki67 revealed a predictive value in NMIBC recurrence. However, the positive TP63 expression did not show any protective effect in NMIBC recurrence. The expression of TP53 and Ki67 could be used to predict the risk of NMIBC recurrence postoperatively.

Loss of MLH1 confers resistance to PI3Kβ inhibitors in renal clear cell carcinoma with SETD2 mutation

Renal clear cell carcinoma (ccRCC) is characterized by frequent mutation in SETD2, which has recently been shown to regulate mismatch repair (MMR). We aim to investigate the association between MMR machinery genes and SETD2 mutation in ccRCC. We exploited the Genomics of Drug Sensitivity in Cancer (GDSC) database to identify selective inhibitors for SETD2 mutant ccRCC cells. We also exploited the Cancer Genome Atlas (TCGA) database to study the association between SETD2 status and MMR-related genes. In vitro studies were performed to validate the in silico findings. Reproduction of the GDSC database revealed four compounds with significant selectivity for SETD2 mutant ccRCC cells, amongst which two compounds targeted PI3Kβ. Phosphorylation of AKT at both S473 and T308 was decreased following PI3Kβ inhibitor treatment in SETD2 mutant ccRCC cells, whereas the basal pAKT level was not changed between mutant and wild-type SETD2. Both decreased MLH1 and increased AKT levels induced lower PMS2, indicating that MMR was mediated by SETD2 via both AKT and MLH1 in ccRCC. Analysis of the TCGA database further revealed high tendency of homozygous co-deletion of SETD2 and MLH1. In the absence of MLH1, suppression of pAKT by PI3Kβ inhibitor was mitigated and inhibition in cell proliferation, invasiveness, migratory ability and tumourigenesis was partially restored. Besides the reported H3K36-trimethylation pathway, we found that SETD2 mutation also mediated MMR via AKT-induced PMS2 decrease and co-loss of MLH1 loss in ccRCC.

The association between polymorphisms in prooxidant or antioxidant enzymes (myeloperoxidase, SOD2, and CAT) and genes and prostate cancer risk in the Chinese population of Han nationality.

BACKGROUND Oxidative stress was associated with prostate cancer (PCa). The expressions of prooxidant or antioxidant enzymes (myeloperoxidase [MPO], superoxide dismutase (SOD2), and catalase (CAT)) have been proved to be related to gene polymorphisms. Our study aimed to evaluate the association between genetic polymorphisms and the risk of PCa. METHODS Genotyping was carried out by genotyping system (MassARRAY iPLEX; Sequenom Inc, San Diego, CA) in 1388 patients with PCa and 1008 cancer-free controls in the Chinese population. RESULTS One SNP of SOD2 (rs5746136; P < .050, odds ratios (OR), 0.8806) was significant. Another SNP was shown to have limited association with the risk of PCa (rs554518; P = .09443) in all SNPs of CAT. In other SNPs, no significant difference was shown between genotype distributions in the patients with PCa and the control group. CONCLUSIONS Our data showed that rs5746136 of SOD2 was associated with susceptibility to PCa in the Chinese population of Han nationality. The possible association between rs8082134 of CAT and PCa risk needs further verification.

Paraneoplastic symptoms: Cachexia, polycythemia, and hypercalcemia are, respectively, related to vascular endothelial growth factor (VEGF) expression in renal clear cell carcinoma

OBJECTIVES To evaluate whether there is a relation between expression of vascular endothelial growth factor (VEGF) and any of the paraneoplastic syndromes (PNS) in clear cell renal cell carcinoma (ccRCC) patients. MATERIALS AND METHODS A total of 667 patients with ccRCC and at least one PNS were included. Thorough history taking, physical examinations, and laboratory tests were used to diagnose PNS. Immunohistochemistry was performed for VEGF evaluation. RESULTS There were 10 different PNS identified in the population. Sixty patients had a single paraneoplastic presentation. In all patients, presence of cachexia (n = 267, P < 0.0001), polycythemia (n = 40, P = 0.0014), and hypercalcemia (n = 48, P = 0.0006) was correlated to VEGF expression. Correlation was neither acquired in Stauffers syndrome, pyrexia, elevated erythrocyte sedimentation rate (ESR), anemia, thrombocytosis, hypertension, neuromyopathy nor obtained within patients with single PNS. CONCLUSIONS Relations between PNS and VEGF expression in renal cell carcinoma (RCC) has not been studied yet. The results we gained hereby can help us further understand the mechanistic of PNS in RCC.