Dataset Information

Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder.

ABSTRACT: Disabled homolog-2 (DAB2) has been reported to be a tumor suppressor gene. However, a number of contrary studies suggested that DAB2 promotes tumor invasion in urothelial carcinoma of the bladder (UCB). Here, we investigated the clinical role and biological function of DAB2 in human UCB. Immunohistochemical staining analysis for DAB2 was carried out on UCB tissue specimens. DAB2 expression levels were compared with clinicopathological factors. DAB2 was knocked-down by small interfering RNA (siRNA) transfection, and then its effects on cell proliferation, invasion, and migration, and changes to epithelial-mesenchymal transition (EMT)-related proteins were evaluated. In our in vivo assays, tumor-bearing athymic nude mice subcutaneously inoculated with human UCB cells (MGH-U-3 or UM-UC-3) were treated by DAB2-targeting siRNA. Higher expression of DAB2 was associated with higher clinical T category, high tumor grade, and poor oncological outcome. The knock-down of DAB2 decreased both invasion and migration ability and expression of EMT-related proteins. Significant inhibitory effects on tumor growth and invasion were observed in xenograft tumors of UM-UC-3 treated by DAB2-targeting siRNA. Our findings suggested that DAB2 expression was associated with poor prognosis through increased oncogenic properties including tumor proliferation, migration, invasion, and enhancement of EMT in human UCB.

SUBMITTER: Itami Y

PROVIDER: S-EPMC7168324 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder.

Itami Yoshitaka Y Miyake Makito M Ohnishi Sayuri S Tatsumi Yoshihiro Y Gotoh Daisuke D Hori Shunta S Morizawa Yosuke Y Iida Kota K Ohnishi Kenta K Nakai Yasushi Y Inoue Takeshi T Anai Satoshi S Tanaka Nobumichi N Fujii Tomomi T Shimada Keiji K Furuya Hideki H Khadka Vedbar S VS Deng Youping Y Fujimoto Kiyohide K

Diagnostics (Basel, Switzerland) 20200120 1

Disabled homolog-2 (<i>DAB2</i>) has been reported to be a tumor suppressor gene. However, a number of contrary studies suggested that DAB2 promotes tumor invasion in urothelial carcinoma of the bladder (UCB). Here, we investigated the clinical role and biological function of DAB2 in human UCB. Immunohistochemical staining analysis for DAB2 was carried out on UCB tissue specimens. DAB2 expression levels were compared with clinicopathological factors. DAB2 was knocked-down by small interfering RN ...[more]

PMID: 31968685

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Project description:BackgroundThe tumor microenvironment (TME) regulates the proliferation and metastasis of solid tumors and the effectiveness of immunotherapy against them. We investigated the prognostic role of TME-related genes based on transcriptomic data of bladder urothelial carcinoma (BLCA) and formulated a prediction model of TME-related signatures.MethodsMolecular subtypes were identified using the non-negative matrix factorization (NMF) algorithm based on TME-related genes from the TCGA database. TME-related genes with prognostic significance were screened with univariate Cox regression analysis and lasso regression. Nomogram was developed based on risk genes. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used for inner and outer validation of the model. Risk scores (RS) of patients were calculated and divided into high-risk group (HRG) and low-risk group (LRG) to compare the differences in clinical characteristics and PD-L1 treatment responsiveness between HRG and LRG.ResultsWe identified two molecular subtypes (C1 and C2) according to the NMF algorithm. There were significant differences in overall survival (OS) (p<0.05), progression-free survival (PFS) (p<0.05), and immune cell infiltration between the two subtypes. A total of eight TME-associated genes (CABP4, ZNF432, BLOC1S3, CXCL11, ANO9, OAS1, FBN2, CEMIP) with independent prognostic significance were screened to build prognostic risk models. Age (p<0.001), grade (p<0.001), and RS (p<0.001) were independent predictors of survival in BLCA patients. The developed RS nomogram was able to predict the prognosis of BLCA patients at 1, 3, and 5 years more potentially than the models of other investigators according to ROC and DCA. RS showed significantly higher values (p = 0.047) in patients with stable disease (SD)/progressive disease (PD) compared to patients with complete response (CR)/partial response (PR).ConclusionsWe successfully clustered and constructed predictive models for TME-associated genes and helped guide immunotherapy strategies.

Project description:BackgroundUrothelial carcinoma of the bladder (UCB) is the most prevalent malignant tumor of the urinary system worldwide, which has a significant recurrence rate despite multiple treatment options available. As a unique and novel copper-dependent programmed cell death mechanism, the comprehensive impact of cuproptosis on the tumor immune microenvironment, clinicopathological characteristics and the prognosis of patients remains largely unclear.MethodsA total of 568 UCB samples were thoroughly examined for cuproptosis patterns using data downloaded from TCGA and GEO, based on 10 cuproptosis-related genes reported previously. Then, the univariate COX regression analysis was performed on the genes that differed across the various patterns. To measure individual cuproptosis pattern, a cuproptosis score system was constructed using a principal component analysis algorithm. To validate the scoring system, immunohistochemical staining was performed on tumor tissues with different pathological grades, and experiments in vitro were conducted about the differentially expressed genes related to prognosis. Finally, the capacity of scoring system to predict the response to immunotherapy was verified by using data from IMvigor 210 cohort.ResultsFour unique cuproptosis clusters and two gene clusters were finally found by the investigation. The clinical features and prognosis of patients, as well as the mRNA transcriptome, pathway enrichment, and immune cell infiltration in TME, varied dramatically between various cuproptosis clusters and gene clusters. To identify individual cuproptosis patterns in UCB patients, we also established a cuproptosis scoring system. After validation with multiple methods, it was indicated that the score system could predict the prognosis of UCB patients and was significantly connected to clinical features such TNM category, tumor grade, molecular type and ultimate survival status. The clinical outcomes of UCB patients were predicted effectively according to the tumor mutation burden in conjunction with the scoring system. Furthermore, we found that the cuproptosis score had a significant correlation with the response to immunotherapy and the sensitivity to chemotherapy.ConclusionThis study revealed the potential impact of cuproptosis on the UCB tumor immune microenvironment and clinical pathological characteristics. The cuproptosis score system could effectively predict the prognosis of patients and the response to chemotherapy and immunotherapy.

Project description:Epithelial membrane protein 1 (EMP1) is a key gene that regulates cell proliferation and metastatic capability in various types of cancer, and serves an important role in tumor-immune interactions. However, the association between EMP1 and clinical prognosis, as well as the presence of tumor-infiltrating lymphocytes in bladder urothelial carcinoma (BLCA) remains unclear. The present study aimed to explore the relationship between EMP1 expression and tumor immune cell infiltration in BLCA. In the present study, EMP1 expression in BLCA was analyzed using the Oncomine database, The Cancer Genome Atlas (TCGA) and the Tumor Immune Estimation Resource (TIMER). The effects of EMP1 on clinical prognosis were evaluated using the Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis. The correlations between EMP1, cancer immune infiltrates and lymphocyte abundance were determined using the TIMER and Tumor immune system interaction database. In addition, correlations between EMP1 expression and gene markers in immune infiltrates were analyzed using cBioportal. The results demonstrated that, compared with adjacent normal tissues, EMP1 was downregulated in BLCA tissues. High expression of EMP1 was significantly associated with poor overall survival (OS) in BLCA cases obtained from TCGA. Multivariate Cox analysis revealed that EMP1 was an independent predictor of OS in patients with BLCA. Gene set enrichment analysis revealed that EMP1 was associated with cancer-related pathways and was positively correlated with the levels of infiltrating CD8+ T cells, macrophages, neutrophils and dendritic cells in BLCA. Further analysis demonstrated that EMP1 was significantly associated with the enrichment of multiple types of lymphocyte. EMP1 expression exhibited a strong correlation with a range of immune markers in BLCA. In conclusion, the results of the present study demonstrated that EMP1 was associated with a poor prognosis in patients with BLCA, and that the levels of immune infiltration and multiple immunomarker groups were associated with EMP1 expression. These results suggested that EMP1 may be used as a predictive biomarker to determine the prognosis and immune infiltration in BLCA.

Dataset Information

Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder.

Publications

Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder.

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