Metastasis Of Bladder Urothelial Carcinoma Research Articles

Clinical value of M1 macrophage-related genes identification in bladder urothelial carcinoma and in vitro validation.

Background: Tumor microenvironment (TME) takes a non-negligible role in the progression and metastasis of bladder urothelial carcinoma (BLCA) and tumor development could be inhibited by macrophage M1 in TME. The role of macrophage M1-related genes in BLCA adjuvant therapy has not been studied well. Methods: CIBERSOR algorithm was applied for identification tumor-infiltrating immune cells (TICs) subtypes of subjects from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data sets. We identified potential modules of M1 macrophages by weighted gene co-expression network analysis (WGCNA). Nomogram was determined by one-way Cox regression and lasso regression analysis for M1 macrophage genes. The data from GEO are taken to verify the models externally. Kaplan-Meier and receiver operating characteristic (ROC) curves validated prognostic value of M1 macrophage genes. Finally, we divided patients into the low-risk group (LRG) and the high-risk group (HRG) based on the median risk score (RS), and the predictive value of RS in patients with BLCA immunotherapy and chemotherapy was investigated. Bladder cancer (T24, 5637, and BIU-87) and bladder uroepithelial cell line (SV-HUC-1) were used for in vitro validation. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to validate the associated genes mRNA level. Results: 111 macrophage M1-related genes were identified using WGCNA. RS model containing three prognostically significant M1 macrophage-associated genes (FBXO6, OAS1, and TMEM229B) was formed by multiple Cox analysis, and a polygenic risk model and a comprehensive prognostic line plot was developed. The calibration curve clarified RS was a good predictor of prognosis. Patients in the LRG were more suitable for programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte associate protein-4 (CTLA4) combination immunotherapy. Finally, chemotherapeutic drug models showed patients in the LRG were more sensitive to gemcitabine and mitomycin. RT-qPCR result elucidated the upregulation of FBXO6, TMEM229B, and downregulation of OAS1 in BLCA cell lines. Conclusion: A predictive model based on M1 macrophage-related genes can help guide us in the treatment of BLCA.

Increased NUSAP1 expression is associated with lymph node metastasis and survival prognosis in bladder urothelial carcinoma

The main route of metastasis of bladder urothelial carcinoma is through lymph nodes; however, its exact mechanism remains unclear. In this study, we found an association of nucleolar and spindle associated protein 1 (NUSAP1) expression with BUC tissues along with lymph node metastasis and the survival prognosis. A total of 178 pathological specimens following radical bladder cancer resection were obtained. NUSAP1 expression was analyzed by immunohistochemistry. We evaluated the correlation between clinicopathological characteristics and NUSAP1 expression. Logistic regression was used to determine the independent variables that influenced lymph node metastasis. Uni- and multi-factorial Cox regression methods were used to determine the prognostic value of NUSAP1 expression in urothelial carcinoma of the bladder. High expression of NUSAP1 in BUC was not significantly related to the patient’s gender, age, or tumor number (p > 0.05), however was significantly associated with pathological grade, tumor diameter, pathological stage, and lymph node metastasis (p < 0.05). Lymph node metastasis was significantly correlated with pathological stage, pathological grade, tumor number, tumor diameter, and NUSAP1 expression (p < 0.05); only NUSAP1 expression was an independent predictor of lymph node metastasis in BUC (OR:1.786, 95% CI 1.229–2.596, p = 0.002). In addition, high NUSAP1 expression was an independent prognostic predictor for BUC. In BUC, NUSAP1 showed high expression and was significantly associated with lymph node metastasis, pathological stage, pathological grade, and tumor diameter. NUSAP1 was an independent predictor of lymph node metastasis and prognosis in BUC; higher expression indicated poorer prognosis of BUC patients.

Thyroid metastasis of bladder urothelial carcinoma: A very rare case

Metastatic disease to the thyroid is a very uncommon situation. The cancers that usually metastasize to the thyroid include the breast, lung, colon and kidney. To our knowledge, metastasis from the bladder to the thyroid is exceedingly rare. Here, we report a case of a unique metastatic transitional cell carcinoma to the thyroid gland three years after total cystectomy.

Screening and identification of potential prognostic biomarkers in bladder urothelial carcinoma: Evidence from bioinformatics analysis

Bladder urothelial carcinoma (BLCA) is a very much invasive urological malignant tumor that results in reduced patient survival. At current, the mechanism of BLCA metastasis is not clear. This study was aimed to explore the prognostic and diagnostic related biomarkers in BLCA and guide the therapy. First, we acquired data of gene expression in non-muscle invasive bladder cancer samples (N = 15) and muscle invasive bladder cancer samples (N = 15) from the Gene Expression Omnibus (GEO) database. Integrated analysis was used to explore differentially expressed genes (DEGs) (up and down regulated genes) between non invasive BLCA samples and invasive BLCA samples. Pathway enrichment analyses and Gene ontology (GO) of DEGs were performed. DEGs were used to construct a protein–protein interaction (PPI) network using Protein Interaction Network Analysis platform (PINA) database, and the modules from PPI network were verified by Cytoscape software and hub genes were extracted. Furthermore, gene regulatory networks were depicted based on miRNAs and TFs with interest target genes. The survival analysis, expression analysis, stage analysis, mutation analysis, immunohistochemical (IHC) analysis, ROC analysis and RT-PCR for the integrated expression score was applied to determine the diagnostic ability of the candidate biomarkers. In total, 900 DEGs that consisted of 455 up regulated and 445 down regulated genes were screened out. The differentially expressed genes were enriched in stearate biosynthesis, metabolic pathways, acetate conversion to acetyl-CoA, focal adhesion, oxoacid metabolic process, mitochondrial matrix, circulatory system development and extracellular matrix, of which pathways and GO terms were associated in the BLCA development. PPI network analysis, demonstrated the interactions between those DEGs, and 10 hub genes (P4HB, APEX1, SIRT5, SRP68, HIP1R, MYC, A2M, MAP1B, HIPK2 and TCF) were extracted from the network and verified by survival analysis, expression analysis, stage analysis, mutation analysis, immunohistochemical (IHC) analysis, ROC analysis, RT-PCR and immune infiltration analysis.. In this study, we highlighted mechanisms underlying the control of BLCA molecular signatures by TFs and miRNAs which their alteration reduce the chance of survival rate in BLCA. These results revealed that the DEGs may serve as candidate essential genes during BLCA metastasis. The 10 hub genes, including P4HB, APEX1, SIRT5, SRP68, HIP1R, MYC, A2M, MAP1B, HIPK2 and TCF, may serve as promising prognostic biomarkers in BLCA metastasis. In conclusion, the present study identifies DEGs and hub genes that may be involved in poor prognosis and early recurrence of BLCA. The expression levels of P4HB, APEX1, SIRT5, SRP68, HIP1R, MYC, A2M, MAP1B, HIPK2 and TCF are of high prognostic value, and may help us understand better the underlying carcinogenesis or progression of BLCA. Further studies are required to elucidate molecular pathogenesis and alteration in signaling pathways for these genes in BLCA.

Development of a novel six-long noncoding RNA signature predicting survival of patients with bladder urothelial carcinoma.

Bladder urothelial carcinoma is a malignant tumor with a high incidence in the uropoietic system. Considerable studies have shown that long noncoding RNA (lncRNA) plays an important role in the development and progression of bladder urothelial carcinoma. In this study, the lncRNA expression and clinical data of 377 bladder urothelial carcinoma patients were obtained from The Cancer Genome Atlas database and differentially expressed lncRNAs in cancer and normal groups were evaluated. Univariate COX and multivariate COX regression analyses of prognosis were performed on differentially expressed lncRNAs in the training data sets, six prognosis-related lncRNAs (LINC02195, LINC01484, LINC01468, SMC2-AS1, AC011298.1, and PTPRD-AS1) were assessed, and a six-lncRNA signature was constructed. The predictive capability of this six-lncRNA signature was validated in the testing data sets and entire data sets. The prognostic ability of the six-lncRNA signature was independent of other clinical elements after multivariate COX regression and stratified analyses of with other clinical elements. We performed functional enrichment analysis with the six prognosis-related lncRNAs. Results of functional enrichment revealed that these prognosis-related lncRNAs might promote the development and metastasis of bladder urothelial carcinoma. In summary, the six-lncRNA signature that we developed could effectively predict the prognosis of bladder urothelial carcinoma patients. This six-lncRNA signature might be a novel independent prognostic marker of bladder urothelial carcinoma. Moreover, it also provides novel insights into the mechanism of bladder urothelial carcinoma.

AB130. The expression and clinical significance of HIF-1α in bladder urothelial carcinoma

ObjectiveTo observe the expression of hypoxia inducible factor-1α (HIF-1α) in bladder urothelial carcinoma (BUC) and the relationship between it with the metastasis of BUC.MethodsExpression of HIF-1α was detected by SP immunohistochemistry in BUC, to find the relationship of HIF-1α with the clinical pathological characteristics and lymph node metastasis of BUC patientsResultsThe positive expression rate of HIF-1α was 75.6% in 90 cases with BUC (68/90), the positive expression rate in 30 cases of normal bladder tissue cells is 6.7% (2/30), compare the two groups, there was a significant difference between their expression (P<0.01). In different pathological grading and clinical staging, and also in lymph node metastasis, its expressive discrepancy was statistically significant (P<0.05)ConclusionsThe HIF-1 α protein of BUC patients with abnormal high expression is closely related to the cancer growth, suggesting that the protein can be used as an important molecular biological behavior and prognosis judgement of BUC cell markers, also has some clinical reference value in the treatment of postoperative follow-up guidance.

A potential role for 6-sulfo sialyl Lewis X in metastasis of bladder urothelial carcinoma

ObjectivesIt is widely accepted that sialyl Lewis X (sLeX) and sialyl Lewis A (sLeA, also known as CA 19-9) glycans expressed on cancer cells function in E-selectin-mediated metastasis. Recently, it was reported that 6-sulfo sLeX glycans detected by the MECA-79 monoclonal antibody are expressed in roughly a quarter of gastric adenocarcinoma cases, and that these cases show a poorer prognosis than MECA-79-negative cases do. The present study was undertaken to assess expression of 6-sulfo sLeX glycans in bladder urothelial carcinoma and evaluate potential clinical implications. Materials and methodsWe analyzed 78 specimens representing bladder urothelial carcinoma, as well as 4 bladder urothelial carcinoma cell lines, by immunostaining with a battery of anticarbohydrate antibodies. We also undertook an E-selectin·IgM chimera binding assay to assess E-selectin binding to 6-sulfo sLeX expressed on bladder urothelial carcinoma cells and performed reverse transcription polymerase chain reaction and complementary DNA transfection to determine which N-acetylglucosamine-6-O-sulfotransferases function in 6-sulfo sLeX biosynthesis in those cells. Finally, we performed double-immunofluorescence staining for MECA-79 and either CD3 or CD8 to evaluate potential association between high endothelial venule (HEV)-like vessels and tumor-infiltrating T lymphocytes. Results6-Sulfo sLeX glycans were expressed in ~20% of bladder urothelial carcinoma cases, particularly in plasmacytoid and micropapillary variants. Positive cells were also bound by E-selectin·IgM chimeras in a calcium-dependent manner. Transcripts encoding N-acetylglucosamine-6-O-sulfotransferase-2 were detected preferentially in HT-1197 bladder urothelial carcinoma cells expressing 6-sulfo sLeX, and transfection of the enzyme complementary DNA into HT-1376 cells, which do not express 6-sulfo sLeX glycans, resulted in cell surface expression of 6-sulfo sLeX. Furthermore, 6-sulfo sLeX glycans were expressed in HEV-like vessels induced in and around lymphocyte aggregates formed near carcinoma cell nests. These HEV-like vessel-associated tumor-infiltrating lymphocytes were composed primarily of CD3+ T cells, with a fraction of CD8+ cytotoxic T cells. ConclusionsOur findings indicate that 6-sulfo sLeX glycans likely play 2 roles in bladder urothelial carcinoma progression: one in lymphocyte recruitment to enhance antitumor immune responses, and the other in E-selectin-mediated tumor cell adhesion to vascular endothelial cells, which is potentially associated with metastasis.

Unusual presentation of cutaneous metastasis from bladder urothelial carcinoma.

Cutaneous metastases from urothelial carcinoma of the bladder are a rare disease. In previous reports, the most common metastatic cutaneous lesions were non-tender nodules on the abdominal skin. We report a patient with bladder urothelial carcinoma with cutaneous metastases initially presenting as right leg and suprapubic lymphedema. Bladder tumor was the incidental finding by magnetic resonance venography. Urothelial carcinoma (clinical stage IV) was diagnosed, and chemotherapy was performed. Extensive painful erythematous plaques with an erysipelas-like appearance located on the suprapubic area, chest and abdomen were noted, and cutaneous metastases were confirmed by histopathology. Subsequently, extensive scrotal and prepuce ulcerative changes developed. This paper reports a rare case of extensive cutaneous metastasis of bladder urothelial carcinoma who presented an interesting clinical course.

High expression of polo-like kinase 1 is associated with the metastasis and recurrence in urothelial carcinoma of bladder

ObjectivesPolo-like kinase 1 (Plk1) has been widely pursued as an oncology target because it is overexpressed in several human tumor types. To investigate whether Plk1 plays a general role in bladder urothelial carcinoma, we examined the expression of Plk1 protein in bladder urothelial carcinoma and cell lines, and analyzed the relationship among Plk1 protein expression, metastasis, and recurrence of urinary bladder urothelial carcinoma. MethodsImmunohistochemistry was used to detect the expression of Plk1 in 120 bladder urothelial carcinoma. Moreover, the expression of Plk1 was analyzed by Western blot in 60 bladder urothelial carcinoma and 21 normal epithelial tissues. MTT assay and flow cytometry and transwell assay were used to examine the proliferative and invasive ability of bladder cancer cells with the treatment of scytonemin (the inhibitor of Plk1). Statistical analysis was used to discuss the association between Plk1 expression and clinicopathologic parameters, tumor metastasis and recurrence, and the proliferative and invasive ability and cell cycle process of the bladder cancer cells. ResultsThere was a significantly higher Plk1expressions in bladder urothelial carcinoma and highly invasive bladder T24 cells than those in bladder normal tissues and the superficial bladder BIU-87 cells. Plk1 expression was positively correlated with histologic grade, pT stage, recurrence, and metastasis. With the increasing concentration of scytonemin, we found that not only the cell proliferation and invasion activity decreased significantly, but also the cell cycle was blocked at G2/M stage. ConclusionPlk1 expression status was closely correlated with important histopathologic characteristics (grades and stages) and the recurrence and metastasis of bladder urothelial carcinomas. Furthermore, Plk1 played an important function on the bladder cancer cells' proliferation by regulating the cancer cell cycle from G1/S to G2/M and probably promoted the invasion and metastasis of bladder cancer.

Expression of Snail in bladder urothelial carcinoma and its relationship with E-cadherin and a subset of T cell Groups

Objective To investigate the expression of Snail in bladder urothelial carcinoma and evaluate its relationship with E-cadherin and a subset of T cell groups.Methods Immunohistochemical method was used to detect the expression of Snail and E-cadherin proteins in tissue from 156 cases of bladder urothelial carcinoma and 80 cases of the para-cancerous mucosa. The proteins expression status was analyzed with clinico-pathological data. Meanwhile, correlations with Snail and CD4+, CD8+, CD4+/CD8+ were analyzed.Results The positive rate of Snail in bladder urothelial carcinoma was 65.4％ , which was significantly higher than that in para-cancerous mucosa (48.8％). The expression of Snail was significantly correlated with the clinical stage, pathological grade, tumor quantity, distant metastasis and tumor recurrence.There was negative correlation between the expression of Snail and E-cadherin in bladder urothelial carcinoma. Positive expression of Snail had a negative correlation with the number of CD4+ and CD4+/CD8+ , whereas it had no significant correlation with the number of CD8+.Conclusions By inhibition of the E-cadherin expression and inducing local immunosuppression, Snail might play an important role in the process of the invasion and metastasis of bladder urothelial carcinoma. Key words: Snail protein; E-cadherin protein; Bladder urothelial carcinoma; Subset of Tcell; Immunohistochemistry