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Cisplatin resistance driver gene CLSPN product is a target for immunotherapy in urothelial carcinoma.

ABSTRACT: Bladder cancer is a major and mortal disease in urological area. Cisplatin is a key drug for bladder cancer especially for muscle invasive cases. In most cases of bladder cancer, cisplatin is effective; however, resistance to cisplatin is critical for patient’s prognosis. Thus, treatment strategy for cisplatin resistant bladder cancer is essential to improve current prognosis. In this study, we established cisplatin resistant bladder cancer line (CR cells) using a urothelial carcinoma line UM-UC-3 cells. We screened potential targets for CR cells and found that claspin is overexpressed in CR cells. Claspin mRNA knockdown revealed that claspin has a role in cisplatin resistance in CR cells. In our previous study, we found HLA-A*02:01-restricted CLSPN peptide by an HLA ligandome analysis. We thus generated CLSPN peptide specific CTL clone and found that CLSPN peptide-specific CTL clone recognized CR cells at higher levels compared with that of UM-UC-3 wild type cells. These findings indicate that claspin is a driver for cisplatin resistance and claspin peptide-specific immunotherapy is effective for cisplatin resistant cases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217413 | GEO | 2024/04/10

REPOSITORIES: GEO

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GRIK2 is a target for bladder cancer stem-like cell-targeting immunotherapy

Project description:Recent studies revealed that treatment resistant cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be targeted by cytotoxic T lymphocytes (CTLs). CTLs recognize antigenic peptide derived from tumor-associated antigens (TAAs), thus identification of tumor-associated antigens (TAAs) expressed in CSCs/CICs is essential. Human leucocyte antigen (HLA) ligandome analysis using mass spectrometry enables analysis of naturally expressed antigenic peptides; however, HLA ligandome analysis requires large scale of sample and it is challenging for CSCs/CICs. In this study, we established novel bladder CSC/CIC model from a bladder cancer cell line UM-UC-3 cells using ALDEFLUOR assay. CSCs/CICs were isolated as aldehyde dehydrogenase (ALDH) high cells and several ALDHhigh clone cells were established. ALDHhigh clone cells were enriched with CSCs/CICs by sphere formation and tumorigenicity in immune deficient mouse. HLA ligandome analysis and gene expression (CAGE) using ALDHhigh clone cells revealed distinctive antigenic peptide repertoire in bladder CSCs/CICs, and we identified GRIK2 derived antigenic peptide is specifically expressed in CSCs/CICs. GRIK2 peptide-specific CTL clone recognized GRIK2-overexpressed UM-UC-3 cells and ALDHhigh clone cells indicating that GRIK2 peptide can be a novel target for bladder CSCs/CICs-targeting immunotherapy.

2021-10-01 | GSE166947 | GEO

Epigenome analysis of parental (native) and 3-bromopyruvate-resistant UM-UC-3 bladder cancer cells

Project description:Genome-wide DNA methylation profiling of parental (native) and 3-bromopyruvate-resistant UM-UC-3 bladder cancer cells. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 450,000 CpGs in treatment-naive and 3-bromopyruvate-resistant UM-UC-3 bladder cancer cells.

2021-05-04 | GSE173764 | GEO

Expression profile of lncRNAs in CSCs and non-CSCs of bladder cancer cell line

Project description:Bladder cancer stem cells (CSCs) contribute to tumorigenesis, recurrence and chemoresistance of bladder cancer. However, the molecular mechanisms underlying their self-renewal are poorly unknown. Long noncoding RNAs (lncRNAs) act as crucial regulators in a lot of human cancers, yet their potential roles and molecular mechanisms in bladder CSCs are poorly understood. The goal of this study is to identify the differentially expressed lncRNAs in bladder CSCs (UM-UC-3 4th spheres), its two differentiation sublines and bladder non-CSCs (UM-UC-3). Our study reveals that deregulation of lncRNAs is involved in the bladder CSCs.

2019-09-22 | GSE107857 | GEO

The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell cycle progression in mouse bladder cancer cells in vitro and in vivo

Project description:PURPOSE: Despite over 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluate the role of Aurora A, identified as an upregulated candidate molecule in bladder cancer, in regulating bladder tumor growth. EXPERIMENTAL DESIGN: Gene expression in human bladder cancer samples was evaluated using RNA microarray and reverse-transcriptase PCR. The specific Aurora kinase A inhibitor MLN8237 (Millennium) was used to determine effects on bladder cancer cell growth using in vitro and in vivo models using malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells. RESULTS: Urothelial carcinoma upregulates a set of 13 mitotic spindle associated transcripts, as compared to normal urothelium, including MAD2L1 (7.6-fold), BUB1B (8.8-fold), Aurora kinases A (5.6-fold) and Aurora kinase B (6.2-fold). Application of MLN8237 (10nM-1µM) to the human bladder tumor cell lines T24 and UM-UC-3 induced dose-dependent G2 cell cycle arrest, aneuploidy, mitotic spindle abnormalities, and apoptosis. MLN8237 arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model (p<0.05). Finally, in vitro combination of MLN8237 with either paclitaxel or gemcitabine produced schedule-dependent synergistic antiproliferative effects in T24 cells when administered sequentially. CONCLUSIONS: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma, and can be exploited with pharmacologic Aurora A inhibition. Future studies that explore the mechanisms of spindle checkpoint failure in bladder cancer and evaluate the therapeutic role of Aurora kinases for bladder cancer patients would be of value. Tissue samples with urothelial cell carcinoma from bladder as well as normal references were collected and the gene expression profiles were compared. No technical replicates.

2013-05-01 | E-GEOD-42089 | biostudies-arrayexpress

The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell cycle progression in mouse bladder cancer cells in vitro and in vivo

2013-05-01 | GSE42089 | GEO

The M1 aminopeptidase NPEPPS is a novel regulator of cisplatin sensitivity

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2024-02-20 | PXD024742 | Pride

Super-enhancer LncRNA expression profile in human bladder cancer cell line and human urothelial immortalized cell line

Project description:To further explore the differential expression profile of super-enhancer long noncoding RNA (LncRNA) in human bladder cancer, we have employed super-enhancer lncRNA microarray expression profiling as a discovery platform to identify potential differential expression profile of super-enhancer lncRNA between human bladder cancer cell (UM-UC-3 cell) and urothelial immortalized cell (SV-HUC-1 cell). Results showed that a large number of differentially expressed super-enhancer lncRNA were found between UM-UC-3 cell and SV-HUC-1 cell. In this study, We verified 5 up-regulated differentially expressed super-enhancer lncRNAs using qPCR, of which the highest fold change is LINC00162. Then we further explored the biological function and mechanism of LINC00162 in bladder cancer in this study.

2020-12-22 | GSE159682 | GEO

NONO-mediated alternative splicing of SETMAR inhibits lymphatic metastasis in bladder cancer

Project description:To explore the molecular mechanism underlying NONO-mediated lymphatic metastasis inhibition in bladder cancer, a genome-wide RNA-sequencing was conducted to compare gene expression profiles of UM-UC-3 cells with NONO knockdown and control.

2020-03-21 | GSE147323 | GEO

APIM-peptide targeting PCNA improves cisplatin therapy in a rat muscle-invasive bladder cancer model

Project description:High mortality rate of muscle-invasive bladder cancer (MIBC) and complexity of disease demand new multi-targeting treatment strategies. Targeting proliferating cell nuclear antigen (PCNA) with a peptide containing the AlkB homologue 2 PCNA interacting motif (APIM), is shown to impair multiple vital cellular stress responses and induce hypersensitivity against several chemotherapeutics in different pre-clinical models. This study examine the anti-cancer efficacy of the novel APIM-peptide drug when combined with cisplatin-based therapies (cisplatin, cisplatin/gemcitabine (GC) and methotrexate/vinblastine/adriamycin/cisplatin (MVAC)) in a panel of bladder cancer (BC) cells and with intravenous cisplatin-therapy in a rat MIBC-model. Furthermore, we explore the molecular mechanisms underlying the observed effects on a genomic, proteomic and metabolomic level using microarray, multiplexed inhibitor bead (MIB)-assay, and targeted mass spectrometric metabolite profiling. The APIM-peptide significantly increased the efficacy of all cisplatin-based therapies in all BC cell lines tested, including a cisplatin resistant cell line and reduced the tumor load in cisplatin treated MIBC-bearing rats. Genome and proteome analysis of APIM-peptide/cisplatin treated BC cells revealed reduced expression of multiple proteins frequently overexpressed in MIBC. Of notice, the EGFR/ERBB2, PI3K/Akt and MAPK signaling pathways and anti-apoptosis were downregulated. We suggest that the anti-cancer effect of the APIM-peptide is through the downregulation of several known oncogenic signaling pathways including anti-apoptosis. Together our results indicate that the APIM-peptide represents a potential improved treatment approach for patients with MIBC.

2018-09-10 | PXD008724 | Pride

Discovery of genes regulated by the metastasis suppressor gene, RhoGDI2

Project description:A number of studies find that metastasis suppressor proteins, including RhoGDI2, may function in part though controlling expression of genes regulating metastasis (reviewed in Smith and Theodorescu, Nature Reviews Cancer, 2009, PMID: 19242414). To uncover systematically gene expression patterns dependent on RhoGDI2 expression, we profiled gene expression in stably transfected control (GFP empty vector) UM-UC-3 bladder carcinoma cells (which have lost endogenous expression of RhoGDI2, as occurs commonly in the progression of bladder cancer PMID: 15173088), as well as stably transfected GFP-tagged RhoGDI2 expressing UM-UC-3 cells. References: Moissoglu K, McRoberts KS, Meier JA, Theodorescu D et al. Rho GDP dissociation inhibitor 2 suppresses metastasis via unconventional regulation of RhoGTPases. Cancer Res 2009 Apr 1;69(7):2838-44. PMID: 19276387 Wu Y, Moissoglu K, Wang H, Wang X et al. Src phosphorylation of RhoGDI2 regulates its metastasis suppressor function. Proc Natl Acad Sci U S A 2009 Apr 7;106(14):5807-12. PMID: 19321744 Smith SC, Theodorescu D. Learning therapeutic lessons from metastasis suppressor proteins. Nat Rev Cancer 2009 Apr;9(4):253-64. PMID: 19242414 Theodorescu D, Sapinoso LM, Conaway MR, Oxford G et al. Reduced expression of metastasis suppressor RhoGDI2 is associated with decreased survival for patients with bladder cancer. Clin Cancer Res 2004 Jun 1;10(11):3800-6. PMID: 15173088 Two paired biological replicates of GFP (control) and GFP-RhoGDI2 (experimental) UM-UC-3 cells were prepared at different times, isolated during log phase growth, and subjected to gene expression profiling using the Affymetrix HG-U133 Plus 2.0 oligonucleotide microarray platform.

2012-04-14 | E-GEOD-35014 | biostudies-arrayexpress

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