Progression Of Human Bladder Cancer Research Articles

MiR-124 exerts tumor suppressive functions on the cell proliferation, motility and angiogenesis of bladder cancer by fine-tuning UHRF1.

UHRF1, an epigenetic factor, is implicated in various cellular processes of tumorigenesis. However, the modulation of UHRF1 expression in human bladder cancer at post-transcriptional levels remains unclear. Here, we report that miR-124 suppresses expression of UHRF1 to affect the progression of human bladder cancer through competitive binding of the same region of its 3'-UTR. We show that compared with corresponding normal tissues, UHRF1 is upregulated and miR-124 is downregulated in bladder cancer tissues, demonstrating an inverse correlation of miR-124 and UHRF1. Quantitative PCR and western blot assay demonstrated that over-expression of miR-124 resulted in the suppression of UHRF1. Furthermore, luciferase assay revealed that miR-124 could control the fate of target gene UHRF1 mRNA by binding 3'-UTR. The rescue experiment confirmed that miR-124 exerted its biological functions by targeting UHRF1. miR-124 over-expression significantly attenuated cellular proliferation, migration, invasion and vasculogenic mimicry in vitro, and tumor growth in vivo. UHRF1 siRNA showed significant inhibitory effects on bladder cancer cells. Collectively, our study demonstrates that miR-124 can impair the proliferation or metastasis of human bladder cancer cells by down-regulation of UHRF1.

Silencing of ATPase Inhibitory Factor 1 Inhibits Cell Growth via Cell Cycle Arrest in Bladder Cancer

Objective: The role of the ATPase inhibitory factor 1 (IF1) is inhibit the hydrolase activity of F₁F_o-ATPase when oxidative phosphorylation is impaired. It has been demonstrated that IF1 is overexpressed in various carcinomas and mediates tumor cell activities, but the detailed mechanisms of IF1-mediated tumor progression and the link between IF1 and cell cycle progression remain unclear. Herein, we aimed to investigate the potential role of IF1 in cell cycle progression of human bladder cancer (BCa). Methods: The expression of IF1 was analyzed by immunohistochemistry in tumor tissues. Western blot was used to detect protein expression in the cells. Cell proliferation was determined by MTT and colony formation assays. The cell cycle was analyzed using flow cytometry. Results: We firstly showed IF1 was overexpressed in BCa. Silencing of IF1 by small interfering RNA led to a significant decrease in cell proliferation and migration in T24 and UM-UC-3 cells. Importantly, IF1 knockdown caused cell cycle arrest at G₀/G₁ stage and decreased the protein level of cyclin E/cyclin-dependent kinases (cdk) 2 and/or cyclin D/cdk4/cdk6. Conclusion: These results suggest the inhibitory effect of IF1 knockdown on BCa cell proliferation is via the suppression of cyclins and cdks related to G₁/S transition and then induction of G₀/G₁ arrest, and firstly indicate IF1 mediates the tumor cell cycle. We concluded that IF1 may be a novel therapeutic target for BCa.

MiR-128 downregulation promotes growth and metastasis of bladder cancer cells and involves VEGF-C upregulation

MicroRNA-128 (miR-128) serves an important role in regulating growth, invasiveness, stem cell-like traits, differentiation and apoptosis of different types of tumor cells. Vascular endothelial growth factor-C (VEGF-C) has been associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis and has previously been reported to have an anti-apoptotic and proliferative role in bladder cancer (BC). To investigate the regulation of miR-128 on VEGF-C expression and their effects on proliferation and metastasis of bladder cancer, T24 and 5637 BC cells were transfected with pre-miR-128, anti-miR-128 and their respective negative control. miR-128 was downregulated in BC tissues and cell lines, while the expression levels of VEGF-C were upregulated. The present results indicated that miR-128 negatively regulated VEGF-C expression in BC T24 and 5637 BC cells. VEGF-C is a direct target of miR-128 in BC cells. Overexpression of miR-128 inhibited cell proliferation, migration and invasion. Knockdown of miR-128 promoted proliferation, migration and invasion in BC cells. Therefore, downregulation mediated malignant progression of BC may be partly attributed to increased VEGF-C expression. Consequently, the findings of the present study provide a molecular basis for the role of miR-128/VEGF-C in the progression of human BC and indicate a novel target for treatment of BC.

Mutation of TGF-β receptor II facilitates human bladder cancer progression through altered TGF-β1 signaling pathway

Tumor cells commonly adapt survival strategies by downregulation or mutational inactivation of TGF-β receptors thereby reversing TGF-β1-mediated growth arrest. However, TGF-β1-triggered signaling also has a protumor effect through promotion of tumor cell migration. The mechanism(s) through which malignant cells reconcile this conflict by avoiding growth arrest, but strengthening migration remains largely unclear. TGF-βRII was overexpressed in the bladder cancer cell line T24, concomitant with point mutations, especially the Glu269 to Lys mutation (G → A). Whilst leaving Smad2/3 binding unaffected, TGF-βRII mutations resulted in the unaffected tumor cell growth and also enhanced cell mobility by TGF-β1 engagement. Such phenomena are perhaps partially explained by the mutated TGF-βRII pathway deregulating the p15 and Cdc25A genes that are important to cell proliferation and CUTL1 gene relevant to motility. On the other hand, transfecting recombinant TGF-βRII-Fc vectors or smad2/3 siRNA blocked such abnormal gene expressions. Clinically, such G → A mutations were also found in 18 patients (n=46) with bladder cancer. Comparing the clinical and pathologic characteristics, the pathologic T category (χ2 trend = 7.404, P<0.01) and tumor grade (χ2 trend = 9.127, P<0.01) tended to increase in the G → A mutated group (TGF-βRII point-mutated group). These findings provide new insights into how TGF-β1 signaling is tailored during tumorigenesis and new information into the current TGF-β1-based therapeutic strategies, especially in bladder cancer patient treatment.

ALKBH2, a novel AlkB homologue, contributes to human bladder cancer progression by regulating MUC1 expression

The ALKBH family of proteins are highly expressed in various types of human cancer where they are involved in tumor growth and progression. However, multiple isoforms of ALKBH exist and the effect of individual isoforms on the development of urinary bladder cancer is unknown, particularly the molecular mechanisms involved in the progression from a noninvasive to invasive phenotype. We examined the role and function of ALKBH2 in human bladder cancer development in vitro and provide the first report that suppression of ALKBH2 in a human urothelial carcinoma cell line, KU7, reduces the expression of the transmembrane mucin protein, MUC1, and induces G1 cell cycle arrest. Moreover, reduction of ALKBH2 suppressed epithelial to mesenchymal transition (EMT) via increasing E-cadherin and decreasing vimentin expression. Transfection of MUC1 siRNA inhibited cell proliferation and EMT to the same extent as ALKBH2 gene silencing in vitro. ALKBH2 knockdown significantly suppressed MUC1 expression and tumor volume of bladder cancers in vivo as assessed in an orthotopic mouse model using ALKBH2 shRNA transfected KU7 cells. Immunohistochemical examination showed high expression levels of ALKBH2 in human urothelial carcinoma samples, especially in high-grade, superficially and deeply invasive carcinomas (pT(1) and >pT(2)), and in carcinoma in situ but not in normal urothelium. This study demonstrates that ALKBH2 is an upstream molecule of the oncoprotein, MUC1, and regulates cell cycle and EMT, resulting in progression of urothelial carcinomas.

Does phosphorylation of cofilin affect the progression of human bladder cancer?

BackgroundWe determined the differently expressed protein profiles and their functions in bladder cancer tissues with the aim of identifying possible target proteins and underlying molecular mechanisms for taking part in their progression.MethodsWe examined the expression of proteins by proteomic analysis and western blot in normal urothelium, non-muscle-invasive bladder cancers (NMIBCs), and muscle-invasive bladder cancers (MIBCs). The function of cofilin was analyzed using T24 human bladder cancer cells.ResultsThe expression levels of 12 proteins were altered between bladder cancers and normal bladder tissues. Of these proteins, 14-3-3σ was upregulated in both NMIBCs and MIBCs compared with controls. On the other hand, myosin regulatory light chain 2, galectin-1, lipid-binding AI, annexin V, transthyretin, CARD-inhibitor of NF-κB-activating ligand, and actin prepeptide were downregulated in cancer samples. Cofilin, an actin-depolymerizing factor, was prominent in both NMIBCs and MIBCs compared with normal bladder tissues. Furthermore, we confirmed that cofilin phosphorylation was more prominent in MIBCs than in NMIBCs using immunoblotting and immunohistochemcal analyses. Epidermal growth factor (EGF) increased the phosphorylation of cofilin and elevated the migration in T24 cells. Knockdown of cofilin expression with small interfering RNA attenuated the T24 cell migration in response to EGF.ConclusionsThese results demonstrate that the increased expression and phosphorylation of cofilin might play a role in the occurrence and invasiveness of bladder cancer. We suspected that changes in cofilin expression may participate in the progression of the bladder cancer.

Expression of a tumor-associated gene, LASS2, in the human bladder carcinoma cell lines BIU-87, T24, EJ and EJ-M3

Homo sapiens longevity assurance homolog 2 of yeast LAG1 (LASS2), a metastasis suppressor gene of human cancer, is the most abundantly expressed member of the ceramide synthase gene family. Expression of LASS2 has been reported in carcinomas of the prostate, liver and breast. However, there has been no report on the expression of LASS2 in human bladder cancer cell lines. In order to investigate the expression and potential role of this new tumor metastasis supressor gene in human bladder cancer, we compared the proliferation, metastasis and invasion among the BIU-87, T24, EJ and EJ-M3 human bladder cancer cell lines. The mRNA expression levels of the LASS2 gene were examined using real-time quantitative PCR (qPCR). The expression levels of LASS1 and LASS3 mRNA were used as references. The protein expression level of the LASS2 gene was detected using western blotting. The most aggressive of these four human cancer cell lines was observed to be EJ-M3. The expression of LASS2 mRNA was significantly correlated with diverse proliferation, metastasis and invasion. The expression levels of LASS1 and LASS3 mRNA were not correlated with these parameters. At the protein level, we observed that the more aggressive the cancer cell line, the lower the LASS2 protein expression level. Therefore, LASS2 expression may be correlated with the development and progression of human bladder cancer and may be a prognostic indicator for this cancer.

CIP2A protein expression in high‐grade, high‐stage bladder cancer

Bladder cancer is one of the most common cancers in the United States. Numerous markers have been evaluated for suitability of bladder cancer detection and surveillance. However, few of them are acceptable as a routine tool. Therefore, there exists a continuing need for an assay that detects the presence of bladder cancer in humans. It would be advantageous to develop an assay with a protein that is associated with the development of bladder cancer. We have identified the cancerous inhibitor of PP2A (CIP2A) protein as a novel bladder cancer biomarker. In this study, Western blot analysis was used to assess the expression level of CIP2A protein in bladder cancer cell lines and bladder cancer patient tissues (n = 43). Our studies indicated CIP2A protein was abundantly expressed in bladder cancer cell lines but not in nontumor epithelial cell lines. Furthermore, CIP2A was specifically expressed in transitional cell carcinoma (TCC) of the bladder tumor tissues but not in adjacent nontumor bladder tissue. Our data showed that CIP2A protein detection in high-grade TCC tissues had a sensitivity of 65%, which is 3.4-fold higher than that seen in low-grade TCC tissues (19%). The level of CIP2A protein expression increased with the stage of disease (12%, 27%, 67%, and 100% for pTa, pT1, pT2, and pT3 tumor, respectively). In conclusion, our studies suggest that CIP2A protein is specifically expressed in human bladder tumors. CIP2A is preferentially expressed in high-grade and high-stage TCC tumors, which are high-risk and invasive tumors. Our studies reported here support the role of CIP2A in bladder cancer progression and its usefulness for the surveillance of recurrence or progression of human bladder cancer.

Transcriptional activation of the Axl and PDGFR-α by c-Met through a ras- and Src-independent mechanism in human bladder cancer

BackgroundA cross-talk between different receptor tyrosine kinases (RTKs) plays an important role in the pathogenesis of human cancers.MethodsBoth NIH-Met5 and T24-Met3 cell lines harboring an inducible human c-Met gene were established. C-Met-related RTKs were screened by RTK microarray analysis. The cross-talk of RTKs was demonstrated by Western blotting and confirmed by small interfering RNA (siRNA) silencing, followed by elucidation of the underlying mechanism. The impact of this cross-talk on biological function was demonstrated by Trans-well migration assay. Finally, the potential clinical importance was examined in a cohort of 65 cases of locally advanced and metastatic bladder cancer patients.ResultsA positive association of Axl or platelet-derived growth factor receptor-alpha (PDGFR-α) with c-Met expression was demonstrated at translational level, and confirmed by specific siRNA knock-down. The transactivation of c-Met on Axl or PDGFR-α in vitro was through a ras- and Src-independent activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathway. In human bladder cancer, co-expression of these RTKs was associated with poor patient survival (p < 0.05), and overexpression of c-Met/Axl/PDGFR-α or c-Met alone showed the most significant correlation with poor survival (p < 0.01).ConclusionsIn addition to c-Met, the cross-talk with Axl and/or PDGFR-α also contributes to the progression of human bladder cancer. Evaluation of Axl and PDGFR-α expression status may identify a subset of c-Met-positive bladder cancer patients who may require co-targeting therapy.

A Novel Human AlkB Homologue, ALKBH8, Contributes to Human Bladder Cancer Progression

We recently identified a novel human AlkB homologue, ALKBH8, which is expressed in various types of human cancers including human urothelial carcinomas. In examining the role and function of ALKBH8 in human bladder cancer development in vitro, we found that silencing of ALKBH8 through small interfering RNA transfection reduced reactive oxygen species (ROS) production via down-regulation of NAD(P)H oxidase-1 (NOX-1) and induced apoptosis through subsequent activation of c-jun NH(2)-terminal kinase (JNK) and p38. However, we also found that JNK and p38 activation resulted in phosphorylation of H2AX (gammaH2AX), a variant of mammalian histone H2A, which contributes to the apoptosis induced by silencing ALKBH8 and NOX-1. Silencing of ALKBH8 significantly suppressed invasion, angiogenesis, and growth of bladder cancers in vivo as assessed both in the chorioallantoic membrane assay and in an orthotopic mouse model using green fluorescent protein-labeled KU7 human urothelial carcinoma cells. Immunohistochemical examination showed high expression of ALKBH8 and NOX-1 proteins in high-grade, superficially and deeply invasive carcinomas (pT(1) and >pT(2)) as well as in carcinoma in situ, but not in low-grade and noninvasive phenotypes (pT(a)). These findings indicate an essential role for ALKBH8 in urothelial carcinoma cell survival mediated by NOX-1-dependent ROS signals, further suggesting new therapeutic strategies in human bladder cancer by inducing JNK/p38/gammaH2AX-mediated cell death by silencing of ALKBH8.

BAMBI gene is epigenetically silenced in subset of high‐grade bladder cancer

The bone morphogenetic protein (BMP) and activin membrane-bound inhibitor (BAMBI) is a transmembrane TGFRI/BMPRI-related pseudoreceptor, antagonizes transforming growth factor (TGF)-beta/BMP signaling by inhibiting the formation of functional authentic receptor complexes (TGFRI/BMPRI and TGFRII/BMPRII). On the assumption that BAMBI gene expression is epigenetically altered during human bladder cancer progression, we screened the expression of BAMBI protein by immunohistochemistry and the methylation status of the BAMBI promoter. In the normal or reactive urothelium, BAMBI expression was mostly overlapped with that of BMPRI, and a similar colocalization pattern was noted in low-grade papillary cancers. In high-grade and invasive cancers, however, mainly two reciprocal immunohistochemical expression patterns were observed: BAMBI-low/BMPRI-high, and BAMBI-high/BMPRI-low, indicating that BAMBI expression is controlled such that it does not interfere with the responsiveness of high-grade cancer cells to TGF-beta/BMP signaling. Moreover, methylation of the BAMBI gene correlated significantly with negative BAMBI expression in bladder tumors. Although BAMBI overexpression significantly increased the number of apoptotic cells in T24 line, knock-down small interfering RNA showed no remarkable change. Cell motility assay revealed that on treatment with either TGF-beta1 or BMP2, T24 and HTB9 lines showed a marked increase in the number of migrated cells which, however, decreased significantly through the forced expression of BAMBI. Since certain subsets of aggressive tumors often promote cell motility, invasion and survival by inducing epithelial-to-mesenchymal transition through TGF-beta/BMP in an autocrine and paracrine manner, hypermethylation of the BAMBI gene promoter that leads to BAMBI gene suppression may be one of the epigenetic events affecting the invasiveness or aggressiveness of bladder cancers.

Identification of differentially expressed genes in human bladder cancer through genome-wide gene expression profiling

Large-scale gene expression profiling is an effective strategy for understanding the progression of bladder cancer (BC). The aim of this study was to identify genes that are expressed differently in the course of BC progression and to establish new biomarkers for BC. Specimens from 21 patients with pathologically confirmed superficial (n = 10) or invasive (n = 11) BC and 4 normal bladder samples were studied; samples from 14 of the 21 BC samples were subjected to microarray analysis. The validity of the microarray results was verified by real-time RT-PCR. Of the 136 up-regulated genes we detected, 21 were present in all 14 BCs examined (100%), 44 in 13 (92.9%), and the other 71 in 12 BCs (85.7%). Of 69 down-regulated genes, 25 were found in all 14 BCs (100%), 22 in 13 (92.9%), and the other 22 in 12 BCs (85.7%). Functional annotation revealed that of the up-regulated genes, 36% were involved in metabolism and 14% in transcription and processing; 25% of the down-regulated genes were linked to cell adhesion/surface and 21% to cytoskeleton/cell membrane. Real-time RT-PCR confirmed the microarray results obtained for the 6 most highly up- and the 2 most highly down-regulated genes. Among the 6 most highly up-regulated genes, CKS2 was the only gene with a significantly greater level of up-regulation in invasive than in superficial BC (p = 0.04). To confirm this result, we subjected all 21 BC samples to real-time PCR assay for CKS2. We found a considerable difference between superficial and invasive BC (p = 0.001). Interestingly, there was a considerable difference between the normal bladder and invasive BC (p = 0.001) and less difference between the normal bladder and superficial BC (p = 0.005). We identified several genes as promising candidates for diagnostic biomarkers of human BC and the CKS2 gene not only as a potential biomarker for diagnosing, but also for staging human BC. This is the first report demonstrating that CKS2 expression is strongly correlated with the progression of human BC.

Enhanced Expression of Peroxiredoxin I and VI Correlates with Development, Recurrence and Progression of Human Bladder Cancer

PRDXs are antioxidant enzymes that have an important role in cell differentiation, proliferation and apoptosis. We investigated whether PRDX I and VI expression is related to bladder cancer. PRDX I and VI mRNA levels were examined in 149 tumor specimens in patients with primary bladder cancer, in 19 specimens with corresponding normal-appearing bladder mucosa surrounding cancer and in 18 with normal bladder mucosa using real-time polymerase chain reaction. PRDX I and VI expression in bladder cancer (0.6644 and 0.1455 pg/ml) was significantly higher than in normal tissue (0.0278 and 0.0542 pg/ml, each p <0.05) and higher than in corresponding normal bladder mucosa surrounding cancer (0.2353 and 0.0304 pg/ml, respectively, each p <0.0005). PRDX I and VI expression was enhanced in patients with no recurrence (0.8148 and 0.2232 pg/ml) and no progression (0.7405 and 0.1716 pg/ml) compared with levels in those with recurrence (0.4314 and 0.0588 pg/ml) and progression (0.4338 and 0.0668 pg/ml, respectively, each p <0.05). PRDX I and VI expression did not correlate with disease-free survival in patients with bladder cancer. Enhanced PRDX I and VI expression is strongly associated with bladder cancer development. Moreover, enhanced PRDX I and VI expression is also positively associated with a low rate of bladder cancer recurrence and progression. It might be useful as a marker for assessing the recurrence or progression of human bladder cancer.

Effects of Transforming Growth Factor-β1 and Its Receptor on the Development, Recurrence and Progression of Human Bladder Cancer

Purpose: We investigated whether the expression levels of Transforming growth factor β1 (TGF-β1) and its receptors were related to the development, recurrence, progression and disease-free survival in the patients with bladder cancer. Materials and Methods: The mRNA levels of TGF-β1 and its receptors were examined in 102 tumor specimens from patients with primary bladder cancer, 29 corresponding normal bladder mucosae specimens surrounding these tumors and 15 normal bladder mucosae specimens by performing quantitative competitive PCR (QC-PCR). The protein levels of TGF-β1 and its receptors were investigated by performing immunohistochemical staining on sections cut from 86 archival bladder tissue paraffin blocks. Results: QC-PCR analysis showed that expressions of TGF-β1, TGF-β receptor I (TGF-βRI) and receptor II (TGF-βRII) in the superficial and low-grade bladder cancers were significantly higher than those in both the corresponding normal bladder mucosae surrounding the cancer (p= 0.0069, 0.0022 and 0.0046, respectively) and the control's normal bladder mucosae (p=0.0014, 0.0125 and 0.0089, respectively). Expressions of TGF-β1 and its receptors were enhanced in the non-recurred and non-progressed patients compared to the recurred cases (p=0.0022, 0.0003 and 0.0001, respectively) and the progressed cases (p=0.0002, <0.0001 and <0.0001, respectively). Patients with high expression of TGF-β1 and its receptors had a significantly higher disease-free survival rate than those patients with low expressions (p=0.0129, 0.0121 and 0.0132, respectively). Conclusions: The enhanced expression of TGF-β1 and its receptors was correlated not only with superficial and low-grade bladder cancer, but also with enhanced patient survival. In conclusion, our findings suggest that the expressions of TGF-β1 and its receptors are useful prognostic markers for a patient's resistance to disease recurrence and/or progression. (Korean J Urol 2006;47:426-435)

Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder

Recepteur d'Origine Nantais (RON) is a distinct receptor tyrosine kinase in the c-met proto-oncogene family. We examined the mutational and expression patterns of RON in eight human uroepithelial cell lines. Biological effects of RON overexpression on cancer cells were investigated in vitro, and the prognostic significance of RON and/or c-met protein (MET) expression was analysed in a bladder cancer cohort (n=183). There was no evidence of mutation in the kinase domain of RON. Overexpression of RON using an inducible Tet-off system induced increased cell proliferation, motility, and antiapoptosis. Immunohistochemical analysis showed that RON was overexpressed in 60 cases (32.8%) of primary tumours, with 14 (23.3%) showing a high level of expression. Recepteur d'Origine Nantais expression was positively associated with histological grading, larger size, nonpapillary contour, and tumour stage (all P<0.01). In addition, MET was overexpressed in 82 cases (44.8%). Co-expressed RON and MET was significantly associated with decreased overall survival (P=0.005) or metastasis-free survival (P=0.01) in 35 cases (19.1%). Recepteur d'Origine Nantais-associated signalling may play an important role in the progression of human bladder cancer. Evaluation of RON and MET expression status may identify a subset of bladder-cancer patients who require more intensive treatment.

779: Gamma-Catenin Gene Hypermethylation Status as a Potential Marker for Human Bladder Cancer Progression

779: Gamma-Catenin Gene Hypermethylation Status as a Potential Marker for Human Bladder Cancer Progression

Reduced expression of metastasis suppressor RhoGDI2 is associated with decreased survival for patients with bladder cancer.

RhoGDI2 was recently shown to be a metastasis suppressor gene in models of bladder cancer. We sought to further understand its importance in human cancer by determining the level of its expression and the distribution of its encoded protein in normal human tissues and cell lines and to evaluate whether its protein expression is a determinant of human bladder cancer progression. RhoGDI2 mRNA and protein expression was evaluated in cell lines and human tissues using Affymetrix and tissue microarrays, respectively. Tissue microarrays represented most human normal adult tissues and material from 51 patients that had undergone radical cystectomy for bladder cancer. In these 51 patients, the chi(2) test was used to test for associations between RhoGDI2 and stage, grade of urothelial carcinoma, histological type, and disease-specific survival status. Cox proportional hazards regression analyses were used to estimate the effect of RhoGDI2 expression level on time to development of metastatic disease and disease-specific survival time, adjusting for grade, stage, and histological type. In normal tissues, there was strong RhoGDI2 protein expression in WBCs, endothelial cells, and transitional epithelium. RhoGDI2 mRNA expression was inversely related to the invasive and metastatic phenotype in human bladder cancer cell lines. In patients with bladder cancer, univariate analysis indicated that reduced tumor RhoGDI2 protein expression was associated with a lower actuarial 5-year disease-free and disease-specific survival (P = 0.01). In addition, patients with tumors that had low or absent RhoGDI2 had a shorter time to disease-specific death (P <or= 0.01). When tumor grade, stage, histological type, and RhoGDI2 staining level were examined using multivariate analysis, RhoGDI2 expression was found to be an independent predictive factor for disease-specific death (P = 0.03). These results suggest that RhoGDI2 is an independent predictor of prognosis for patients with bladder cancer and provide clinical evidence in support of its involvement in cancer metastasis.

737: Single-Nucleotide Polymorphism of Ninjurin Gene is Associated with Higher Risk for Human Bladder Cancer Progression

You have accessJournal of UrologyDiscussed Poster, Monday, May 10, 2004, 8:00 am - 12:00 pm1 Apr 2004737: Single-Nucleotide Polymorphism of Ninjurin Gene is Associated with Higher Risk for Human Bladder Cancer Progression Leopolda A. Ribeiro-Filho, Pedro Guimarães, Iran A. Da Silva, Cesar da Camara Ferreira, Rogerio A. Santos, Hiroaki Shiina, Rajvir Dahiya, Emmanuel Dias Neto, Sami Arap, and Alvaro S. Sarkis Leopolda A. Ribeiro-FilhoLeopolda A. Ribeiro-Filho More articles by this author , Pedro GuimarãesPedro Guimarães More articles by this author , Iran A. Da SilvaIran A. Da Silva More articles by this author , Cesar da Camara FerreiraCesar da Camara Ferreira More articles by this author , Rogerio A. SantosRogerio A. Santos More articles by this author , Hiroaki ShiinaHiroaki Shiina More articles by this author , Rajvir DahiyaRajvir Dahiya More articles by this author , Emmanuel Dias NetoEmmanuel Dias Neto More articles by this author , Sami ArapSami Arap More articles by this author , and Alvaro S. SarkisAlvaro S. Sarkis More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)37986-2AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "737: Single-Nucleotide Polymorphism of Ninjurin Gene is Associated with Higher Risk for Human Bladder Cancer Progression." The Journal of Urology, 171(4S), pp. 195–196 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 171Issue 4SApril 2004Page: 195-196 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Leopolda A. Ribeiro-Filho More articles by this author Pedro Guimarães More articles by this author Iran A. Da Silva More articles by this author Cesar da Camara Ferreira More articles by this author Rogerio A. Santos More articles by this author Hiroaki Shiina More articles by this author Rajvir Dahiya More articles by this author Emmanuel Dias Neto More articles by this author Sami Arap More articles by this author Alvaro S. Sarkis More articles by this author Expand All Advertisement PDF downloadLoading ...

211 Increasing expression level of ETS-1 via HIF-1α induces the angiogenesis and invasiveness human bladder cancer: It may be one of useful molecular markers to determine the progression of human bladder cancer

211 Increasing expression level of ETS-1 via HIF-1α induces the angiogenesis and invasiveness human bladder cancer: It may be one of useful molecular markers to determine the progression of human bladder cancer

Ras signal transduction in carcinogenesis and progression of bladder cancer: molecular target for treatment?

Ras oncogenes are considered to play a key role in the carcinogenesis and progression of human bladder cancer. The oncogenes code for the Ras p21 proteins, which localize in the internal part of the cell membrane and act as molecular switches to mediate downstream signaling from a variety of extracellular stimuli. Activation of Ras proteins induces the constitutive activation of downstream kinase cascades, which results in continuous mitogenic signaling and transformation of immortalized cells in human bladder cancer. Therefore inactivation of the activated Ras function might be effective for the development of a novel treatment strategy against human bladder cancer. Recently several ways to suppress Ras activities, including inhibitors of Ras signal transduction and a ras suppressor mutant, have been reported. Here we review the current concepts of the basic mechanisms of the intracellular Ras signaling pathway and ras activation in the carcinogenesis and progression of human bladder cancer and discuss clinical potentials of their therapeutic interventions.