Pathogenesis Of Bladder Cancer Research Articles

The Dependence between Urinary Levels of Angiogenesis Factors, 8-Iso-prostaglandin F2α, ɣ-Synuclein, and Interleukin-13 in Patients with Bladder Cancer: A Pilot Study.

During the last decade, a significant increase in the incidence of bladder cancer (BC) has been observed. Angiogenesis plays a key role in the process of tumor growth and metastasis. Additionally, the participation of oxidative stress and chronic inflammation in BC pathogenesis is indicated. The aim of the study was to evaluate the urinary levels of parameters of angiogenesis, stimulating angiogenin (ANG) and inhibiting angiostatin (ANGST), 8-iso-prostaglandin F2α (8-iso-PGF2α) as a marker of oxidative stress, ɣ-synuclein (SNCG) as a cancer progression parameter, and interleukin-13 (IL-13) as an anti-inflammatory immunomodulator. The levels of ANG, ANGST, 8-iso-PGF2α, SNCG, and IL-13 in the urine of BC patients and healthy controls were measured by the enzyme-linked immunosorbent assay. These parameters were examined in the whole group of BC patients and in subgroups depending on the clinical stage: nonmuscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC); histopathologic malignancy: low grade (LG) and high grade (HG) and in primary and recurrent BC. Significantly, higher urinary parameters were found in BC patients in comparison to controls. Levels of all parameters increased with the development of cancer, with the exception of 8-iso-prostaglandin F2α, in which the level was higher in the early stages of the disease, but these differences were not statistically significant. Some correlations have been demonstrated between parameters in BC patients. Based on the receiver operating characteristic curves, ANG and ANGST had the best diagnostic value for BC. The obtained results indicate the important role of the examined parameters of angiogenesis, oxidative stress, and inflammation in the pathogenesis and development of BC. It is reasonable to continue research in order to thoroughly assess the impact of various associated processes on the course of BC. It is also important to carry out similar tests in patients with other urological diseases.

FAT10 promotes the progression of bladder cancer by upregulating HK2 through the EGFR/AKT pathway

The ubiquitin-like protein FAT10 and the hexokinase protein HK2 play vital regulatory roles in several cellular processes. However, the relationship between these two proteins and their role in the pathogenesis of bladder cancer are not well understood. Here, we found that FAT10 and HK2 protein levels were markedly higher in bladder cancer tissues than in normal adjacent tissues. In addition, RNAi-mediated silencing of FAT10 led to reduced HK2 levels and suppressed bladder cancer progression in vivo and in vitro. The results of our in vivo and in vitro experiments revealed that HK2 is critical for FAT10-mediated progression of bladder cancer. The current study demonstrated that FAT10 enhanced the progression of bladder cancer by positively regulating HK2 via the EGFR/AKT pathway. Based on our findings, FAT10 is believed to stabilize EGFR expression by modulating its degradation and ubiquitination. The results of the current study indicate that there is a correlation between FAT10 and HK2 in the progression of bladder cancer. In addition, we identified a new pathway that may be involved in the regulation of HK2. These findings implicate dysfunction of the FAT10, EGFR/AKT, and HK2 regulatory circuit in the progression of bladder cancer.

Establishment of a bladder cancer cell line expressing both mesenchymal and epithelial lineage-associated markers

Several experimental models including patient biopsies, animal models, and cell lines have been recommended to study the mechanism of bladder cancer development. After several passages in culture, cell lines lose some original features, and no longer resemble the cells of their original tumor. This makes it necessary to establish various cell lines. In an attempt to establish a new cell line for bladder cancer, JAM-ICR (RRID: CVCL_A9QB) was derived from a 64-year-old man diagnosed with a high-grade tumor. This cell line was characterized in multiple experiments involving morphological studies, immunophenotyping (by immunohistochemistry and flow cytometry), karyotyping, short tandem repeat analysis, colony-forming assays, migration and invasion assays, and chemosensitivity to anti-cancer drugs. JAM-ICR cells are pale with an irregular polygonal shape, and show some similarities to mesenchymal stem cells but with a wider shape and shorter arms. Phenotypic assessment demonstrated the simultaneous expression of mesenchymal-(vimentin, desmin, CD29, CD90, and CD106) and epithelial lineage (pan-cytokeratin) markers, which supports a phenotype similar to epithelial-mesenchymal transition for this cell line. JAM-ICR displayed high metastatic potential and stem-like properties, i.e., self-renewal, colony forming, and the coexpression of TRA-1 with CD44 and CD166. Furthermore, this cell line was significantly more resistant to doxorubicin in comparison to the 5637 cell line. These features make JAM-ICR a new bladder cancer cell line with metastatic potential and stem-like properties, which may be potentially useful as a model to elucidate the molecular and cellular mechanisms of bladder cancer pathogenesis or evaluate new drugs.

Microarray Expression Profiles and Bioinformatics Analyses Reveal Aberrant Circular RNAs Expression in Bladder Cancer.

BackgroundIncreasing evidence shows that circular RNAs (circRNAs) are involved in many biological processes, functioning as microRNA (miRNA) sponges. The aim of this study is to identify differentially expressed circRNAs in bladder cancer (BCa).MethodsThe transcriptome of circRNAs in BCa was assayed by microarray. Quantitative real-time PCR was performed to verify the results. Then, potential miRNA response elements (MREs) between circRNAs and miRNAs were predicted. Pathway and ontology enrichment analyses were performed to identify mechanisms related to the gene regulation of differentially expressed circRNAs.ResultsThree hundred and eighty-six up-regulated and 394 down-regulated circRNAs were identified, and their potential MREs were predicted in BCa.ConclusionThe differentially expressed circRNAs indicate that circRNAs could play important roles in the molecular pathogenesis of BCa.

Serum LUCAT1 implicates the pathogenesis of muscle-invasive bladder cancer via targeting miR-199a-5p and miR-199b-5p.

Muscle-invasive bladder cancer (MIBC) is a common malignancy of urinary system cancers, accounting for about 1/3 of all newly diagnosed bladder cancer cases. Due to its strong metastasis, the 5-year survival of MIBC is less than 50%, and in serious cases, the overall survival of metastatic bladder cancer patients is about 1.3years. LncRNAs, a type of non-coding RNAs defined as the transcripts exceeding 200 nucleotides in length, are frequently aberrant in multiple cancers including cervical, ovarian, breast and bladder cancers. Recently, LUCAT1 (short for lung cancer-associated transcript 1), a lncRNA first reported to be involved in smoking-related lung cancer, has been observed to exhibit crucial roles in the epithelial-to-mesenchymal transition (EMT), migration and invasion processes of clear cell renal cell carcinoma (ccRCC) and colorectal cancer. However, whether it involves in the pathogenesis of MIBC remains underexplored. In the present study, LUCAT1 was up-regulated in the serum samples of MIBC patients and bladder cancer cell lines, as assessed using real-time PCR. Our in vitro data (including wound healing and trans-well assays) showed that LUCAT1 was required for the proliferation, EMT, migration and invasion processes of T24 cells. Moreover, LUCAT1 directly targeted miR-199a-5p and miR-199b-5p, as affirmed using the luciferase reporter assay, and manipulation of LUCAT1 significantly suppressed miR-199a-5p and miR-199b-5p. Collectively, our findings highlight an axis of LUCAT1/miR-199a/b-5p in MIBC pathogenesis. Therefore, LUCAT1 may possibly be a promising candidate for diagnostic biomarker and therapeutic target of MIBC.

Proteomic Analysis of Exosomes for Discovery of Protein Biomarkers for Prostate and Bladder Cancer.

Extracellular vesicles (EVs) are released by nearly all cell types as part of normal cell physiology, transporting biological cargo, including nucleic acids and proteins, across the cell membrane. In pathological states such as cancer, EV-derived cargo may mirror the altered state of the cell of origin. Exosomes are the smaller, 50–150 nanometer-sized EVs released from fusion of multivesicular endosomes with the plasma membrane. Exosomes play important roles in cell-cell communication and participate in multiple cancer processes, including invasion and metastasis. Therefore, proteomic analysis of exosomes is a promising approach to discover potential cancer biomarkers, even though it is still at an early stage. Herein, we critically review the advances in exosome isolation methods and their compatibility with mass spectrometry (MS)-based proteomic analysis, as well as studies of exosomes in pathogenesis and progression of prostate and bladder cancer, two common urologic cancers whose incidence rates continue to rise annually. As urological tumors, both urine and blood samples are feasible for noninvasive or minimally invasive analysis. A better understanding of the biological cargo and functions of exosomes via high-throughput proteomics will help provide new insights into complex alterations in cancer and provide potential therapeutic targets and personalized treatment for patients.

Treatment of muscle-invasive and advanced bladder cancer in 2020.

Bladder cancer accounts for nearly 170,000 deaths worldwide annually. For over 4 decades, the systemic management of muscle-invasive and advanced bladder cancer has primarily consisted of platinum-based chemotherapy. Over the past 10 years, innovations in sequencing technologies have led to rapid genomic characterization of bladder cancer, deepening our understanding of bladder cancer pathogenesis and exposing potential therapeutic vulnerabilities. On the basis of its high mutational burden, immune checkpoint inhibitors were investigated in advanced bladder cancer, revealing durable responses in a subset of patients. These agents are now approved for several indications and highlight the changing treatment landscape of advanced bladder cancer. In addition, commonly expressed molecular targets were leveraged to develop targeted therapies, such as fibroblast growth factor receptor inhibitors and antibody-drug conjugates. The molecular characterization of bladder cancer and the development of novel therapies also have stimulated investigations into optimizing treatment approaches for muscle-invasive bladder cancer. Herein, the authors review the history of muscle-invasive and advanced bladder cancer management, highlight the important molecular characteristics of bladder cancer, describe the major advances in treatment, and offer future directions for therapeutic development.

A novel risk score based on a combined signature of 10 immune system genes to predict bladder cancer prognosis

Bladder cancer (BC) is a common internal malignant tumor with a poor prognosis worldwide. There is an urgent need to better understand the pathogenesis and progression of BC and to find useful biomarkers for diagnosis and prognosis. This study was aimed at developing a potential immunogenomic prognostic signature for BC patients. To identify possible immune-system-related genes (IRGs) whose parameters predict the survival of BC patients, we chose 371 BC patients and analyzed differentially expressed IRGs from The Cancer Genome Atlas (TCGA) datasets. We then derived a 10-IRG formula, including MMP9, RBP7, PDGFRA, AHNAK, OAS1, OLR1, RAC3, SLIT2, IGF1, and AGTR1, to estimate BC prognosis. To validate the mRNA levels of these IRGs, we performed quantitative PCR and found that the expression of these genes almost matched the corresponding mRNA expression levels in TCGA. Furthermore, we validated the prognostic value of the new risk model using two external datasets from Gene Expression Omnibus: GSE13507 (n = 165) and GSE32894 (n = 224). Our data pointed to a significant correlation between the risk model and patients’ prognosis. Bioinformatic analysis revealed that products of the IRGs have possible effects on tumor immune processes such as an inflammatory response and cytokine-cytokine receptor interaction. Finally, assessment of the clinical value of the immune-system–based risk signature showed that several of these IRGs were differentially expressed between patients with different clinical characteristics: a high risk score positively correlated with female sex, advanced tumor stage, more advanced T stage, and lymph node metastasis. This immunogenomic signature may represents a reliable prognostic tool for BC and can help to design an individualized immunotherapy.

Parasite-bacteria interrelationship.

Parasites and bacteria have co-evolved with humankind, and they interact all the time in a myriad of ways. For example, some bacterial infections result from parasite-dwelling bacteria as in the case of Salmonella infection during schistosomiasis. Other bacteria synergize with parasites in the evolution of human disease as in the case of the interplay between Wolbachia endosymbiont bacteria and filarial nematodes as well as the interaction between Gram-negative bacteria and Schistosoma haematobium in the pathogenesis of urinary bladder cancer. Moreover, secondary bacterial infections may complicate several parasitic diseases such as visceral leishmaniasis and malaria, due to immunosuppression of the host during parasitic infections. Also, bacteria may colonize the parasitic lesions; for example, hydatid cysts and skin lesions of ectoparasites. Remarkably, some parasitic helminths and arthropods exhibit antibacterial activity usually by the release of specific antimicrobial products. Lastly, some parasite-bacteria interactions are induced as when using probiotic bacteria to modulate the outcome of a variety of parasitic infections. In sum, parasite-bacteria interactions involve intricate processes that never cease to intrigue the researchers. However, understanding and exploiting these interactions could have prophylactic and curative potential for infections by both types of pathogens.

Quantitative Proteomics of Urinary Bladder Cancer Cell Lines Identify UAP1 as a Potential Therapeutic Target.

Bladder carcinoma (BC) incidence and mortality rates are increasing worldwide. The development of novel therapeutic strategies is required to improve clinical management of this cancer. Aberrant protein expression may lead to cancer initiation and progression. Therefore, the identification of these potential protein targets and limiting their expression levels would provide alternative treatment options. In this study, we utilized a liquid-chromatography tandem mass spectrometry-based global proteomics approach to identify differentially expressed proteins in bladder cancer cell lines. A total of 3913 proteins were identified in this study, of which 479 proteins were overexpressed and 141 proteins were downregulated in 4 out of 6 BC cell lines when compared with normal human urothelial cell line (TERT-NHUC). We evaluated the role of UDP-N-acetylhexosamine pyrophosphorylase (UAP1) in bladder cancer pathogenesis. The silencing of UAP1 led to reduction in proliferation, invasion, colony formation and migration capability of bladder cancer cell lines. Thus, our study reveals UAP1 as a promising therapeutic target for bladder cancer.

Non-coding RNA in bladder cancer.

Bladder cancer is the tenth most common cancer worldwide and has been associated with high mortality and morbidity. Although the treatment of bladder cancer is based on well-defined tumor classifications and gradings, patients still experience different clinical response. The heterogeneity of this disease calls for substantial research with more in-depth molecular characterization, with the hope of identifying new diagnostic and treatment options. In recent years, non-coding RNAs (ncRNAs), particularly, microRNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNAs (circRNAs) were found to be associated with bladder cancer occurrence and development. This review highlights the recent findings concerning ncRNAs and their relevance to the pathogenesis of bladder cancer. This may provide a foundation for developing highly specific diagnostic tools and more robust therapeutic strategies in the future.

Kdm6a Deficiency Activates Inflammatory Pathways, Promotes M2 Macrophage Polarization, and Causes Bladder Cancer in Cooperation with p53 Dysfunction.

Epigenetic deregulation is deeply implicated in the pathogenesis of bladder cancer. KDM6A (Lysine (K)-specific demethylase 6A) is a histone modifier frequently mutated in bladder cancer. However, the molecular mechanisms of how KDM6A deficiency contributes to bladder cancer development remains largely unknown. We hypothesized that clarification of the pathogenic mechanisms underlying KDM6A-mutated bladder cancer can help in designing new anticancer therapies. We generated mice lacking Kdm6a in the urothelium and crossed them with mice heterozygous for p53, whose mutation/deletion significantly overlaps with the KDM6A mutation in muscle-invasive bladder cancer (MIBC). In addition, BBN (N-butyl-N-(4-hydroxybutyl) nitrosamine), a cigarette smoke-like mutagen, was used as a tumor-promoting agent. Isolated urothelia were subjected to phenotypic, pathologic, molecular, and cellular analyses. The clinical relevance of our findings was further analyzed using genomic and clinical data of patients with MIBC. We found that Kdm6a deficiency activated cytokine and chemokine pathways, promoted M2 macrophage polarization, increased cancer stem cells and caused bladder cancer in cooperation with p53 haploinsufficiency. We also found that BBN treatment significantly enhanced the expression of proinflammatory molecules and accelerated disease development. Human bladder cancer samples with decreased KDM6A expression also showed activated proinflammatory pathways. Notably, dual inhibition of IL6 and chemokine (C-C motif) ligand 2, upregulated in response to Kdm6a deficiency, efficiently suppressed Kdm6a-deficient bladder cancer cell growth. Our findings provide insights into multistep carcinogenic processes of bladder cancer and suggest molecular targeted therapeutic approaches for patients with bladder cancer with KDM6A dysfunction.

MP61-13 DO URINARY-BASED MOLECULAR BIOMARKER HAVE THE ABILITY TO PREDICT THE GRADE OF NON-MUSCLE INVASIVE BLADDER CANCER GRADE?

INTRODUCTION AND OBJECTIVE: Micro-RNA155 (mir-155), MicroRNA-200b (mir-200b), human telomerase reverse transcriptase (hTERT), and E2F3 transcription factor had a role in bladder cancer pathogenesis. We aim to assess their role in diagnosis the non-muscle invasive bladder cancer (NMIBC) grade compared to histopathological results. METHODS: A registered prospective trial (NCT03591367) for 64 NMIBC patients. From voided urine samples, total RNA extract from sedimented urothelial cells were analysed by a reverse transcriptase-polymerase chain reaction assay for the presence of mir-155, mir-200b, hTERT and E2F3 transcript. A receiver operating characteristics (ROC) was plotted in order to choose the best cut-off point. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each test. RESULTS: Patients demographic were comparable (table 1). The expression levels of the mir-155 didn’t show difference between high grade (HG) and low grade (LG) (p=0.06) (table 1). Both mir-155 and mir-200b had the lowest AUC (table 2). E2F3 and hTERT expression in urine was higher in HG NMIBC group than in LG NMIBC (P < 0.001) (table 1). The sensitivity, specificity, accuracy of E2F3 were 86%, 76.2%, and 82.8%, respectively. The sensitivity, specificity, accuracy of hTERT were 86%, 66.7%, and 79.7%, respectively (table 2 and figure 1). CONCLUSIONS: As molecular urinary biomarkers; E2F3 and hTERT have the highest potential for prediction of the grade of NMIBC to either low or high grade.Source of Funding: No

Deciphering the impact of missense mutations on structure and dynamics of SMAD4 protein involved in pathogenesis of gall bladder cancer

Gall bladder cancer (GBC) is the most common malignancy of biliary tract cancer associated with high mortality rate and poor prognosis due to lack of suitable biomarkers. In this study, we explored the structural and functional effects of different missense mutations occurs in SMAD4 that was associated with the development of GBC. We utilized in silico methods to predict the harmful effects of nonsynonymous missense mutations and monitored the stability of protein. We found that all mutations (D351N, G352E, R361C, R361H, E526Q) associated with SMAD4 were deleterious in nature resulting in the formation of deformed or unstable protein structure. Molecular dynamics simulation studies revealed how these mutations affect protein stability, structure, conformation and function. We observed, different mutants increase the compactness and rigidity of SMAD4 protein, alter secondary structure composition, decrease the surface area and protein-ligand interaction and affect its conformation. Findings of current work indicated that the analyzed mutations might affect the structure of protein and its caliber to interact with other molecules, which probably related to functional impairment of SMAD4 upon D351N, G352E, R361C, R361H, E526Q mutations and their involvement in cancer. Hence, the present study has significance of rational drug design and further increase our understanding of GBC development. Communicated by Ramaswamy H. Sarma

Spontaneous and Chemically-induced Bladder Cancer Animal Model

Investigations using animal model systems have been enlightening us with the biology underpinning the development of bladder cancer besides strengthening the existing therapy to improve the clinical outcome in patients. To date, spontaneous and chemical inductions are the classical methods in the generation of animal models of bladder cancer. Attributed to many benefits such as simple protocols and lower maintenance cost, these animal models are widely applied in the investigations of bladder cancer pathogenesis and screening of therapeutic drug. In this review, we give an overview of spontaneous- and chemically-induced bladder cancer animal models accompanying by the pros and cons of these two types of models. Furthermore, various chemical carcinogens used in the induction are discussed with the potential benefits and pitfalls in the establishment of animal models. This review will provide insightful information about the selection of the correct method in establishing the animal models of bladder cancer which are instrumental for studying potential therapeutic agents that target bladder cancer.

The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer.

CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.

Identification and Validation of an Immune-Related Gene-Based Prognostic Index for Bladder Cancer

Background: Bladder cancer (BLCA) is a common malignant tumour of the urinary system. Knowledge of the mechanism of and treatment methods for BLCA remain limited. Methods: Robust rank aggregation was used to integrate five GEO bladder cancer microarray datasets for identifying differentially expressed genes (DEGs) between NMIBC and MIBC. An immune-related gene (IRG)-based prognostic index (IRGPI) was constructed using multivariate analysis. The reliability of the IRGPI was evaluated using independent datasets, and correlations between the IRGPI and clinicopathological characteristics as well as the immune microenvironment were evaluated. Finally, a nomogram was established to evaluate patient prognosis with BLCA. Findings: We identified 154 DEGs related to the degree of BLCA infiltration, including 24 IRGs. Missense mutation was the most common mutation type in IRGs. Ten hub IRGs were identified by protein-protein interaction network analysis. GSEA and GSVA of two novel BLCA-related genes (TYROBP and FCER1G) revealed that they were related to immunity. Nine survival-related IRGs were identified and their potential regulation by transcription factors was analysed. An independent IRGPI (CTSE, CXCL10, FAM3B, MMP9, OLR1, and S100P) was established, and was confirmed to be related to tumour stage, tumour grade, T stage, and N stage. The nomogram could effectively predict the prognosis of BLCA patients. Importantly, the IRGPI reflected infiltration by several types of immune cells. Interpretation: Our data provide new insights in the pathogenesis of BLCA and target genes for immunotherapy. The application of molecular markers for hierarchical prediction paves the way to precision medicine. Funding: This study was financially supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant number: 2018-I2M-1-002) and the Beijing Hospital Clinical Research 121 Project (BJ-2018-090). Declaration of Interest: The authors have declared no competing interests.

Long Non-Coding RNA BCAR4 Binds to miR-644a and Targets TLX1 to Promote the Progression of Bladder Cancer.

BackgroundBladder cancer is a serious threat to human health. It is meaningful to study the pathogenesis of bladder cancer. Long non-coding RNAs (lncRNAs) are reported to promote or inhibit bladder cancer development. However, the role of lncRNA BCAR4 in the regulation of bladder cancer remains unclear.PurposeThis study was to explore the role of lncRNA BCAR4 in the progression of bladder cancer cell.MethodsRT-PCR was used to examine the expression of BCAR4 and miR-644a. CCK8 assay, colony formation assay, Transwell assay were used to detect the progression of bladder cancer cells after transfecting of indicated plasmids.ResultsThe expression of BCAR4 was higher in bladder cancer cell lines than normal urothelial cell line. Moreover, the expression of BCAR4 was associated with the advanced stage and metastasis of bladder cancer. Through knockdown of BCAR4, we discovered that knockdown of BCAR4 significantly decreased the proliferation, migration and invasive abilities of bladder cancer cells. Mechanically, we showed that BCAR4 can bind to miR-644a directly and targets TLX1. Moreover, we also showed that miR-644a was also highly expressed in bladder cancer cells and inhibition of miR-644a or overexpression of TLX1 can increased the migration abilities of bladder cancer caused by knockdown of BCAR4.ConclusionWe showed that BCAR4 sponged miR-644a to modulate the expression of TLX1 and promote bladder cancer development.

Copper and zinc levels in plasma and cancerous tissues and their relation with expression of VEGF and HIF-1 in the pathogenesis of muscle invasive urothelial bladder cancer: a case-controlled clinical study.

To evaluate Cu and Zn levels in bladder cancer (BC) patients and their relationship with expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1). Plasma levels of Cu and Zn were determined in 66 transitional bladder cell carcinoma patients (BC group) and 60 matched controls. The concentration of Cu and Zn as well as the expressions of both VEGF and HIF-1 were also estimated in cancerous and non-cancerous bladder tissues in the BC group. The results showed that plasma Cu and Cu/Zn ratio were significantly higher in BC group when compared with the control group. In contrast, the plasma Zn in BC group was significantly lower than in the controls. Comparing levels of Cu and Zn in cancerous and non-cancerous bladder tissues among the BC group indicated a significantly higher Cu levels in the cancerous tissues, while Zn levels was significantly lower. There were higher expressions of both VEGF and HIF-1 in the cancerous samples. Moreover, the Cu concentration in cancerous tissues was significantly correlated with expressions of VEGF and HIF-1. Logistic regression analysis revealed that the increase in plasma Cu/Zn ratio and plasma Cu and the decrease in plasma Zn may be risk factors for development of bladder cancer. We concluded that alteration of plasma and bladder tissue levels of both Cu and Zn is correlated with pathogenesis of bladder cancer. The increase in Cu level in cancerous tissues of BC group has an important role in angiogenesis in bladder cancer cells.

Re: 5-Methylcytosine Promotes Pathogenesis of Bladder Cancer through Stabilizing mRNAs

Re: 5-Methylcytosine Promotes Pathogenesis of Bladder Cancer through Stabilizing mRNAs