Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA320752 | ENA |
REPOSITORIES: ENA
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Project description:This study shows for the first time that the FOXP3Î3 isoform is preferentially expressed in bladder cancer and induces a more aggressive and luminal isoform is preferentially expressed in bladder cancer and induces a more aggressive and luminal regulation of cancer differentiation and the plasticity amongst cancer subtypes which can be leveraged to optimize therapeutic regimens. These findings also identify a novel molecular marker as a putative companion diagnostic to guide therapy and target to undermine chemotherapy resistance. examination of RNA-Seq in two bladder cancer cell lines
2016-08-05 | E-GEOD-81157 | biostudies-arrayexpress
Project description:This study shows for the first time that the FOXP3Δ3 isoform is preferentially expressed in bladder cancer and induces a more aggressive and luminal isoform is preferentially expressed in bladder cancer and induces a more aggressive and luminal regulation of cancer differentiation and the plasticity amongst cancer subtypes which can be leveraged to optimize therapeutic regimens. These findings also identify a novel molecular marker as a putative companion diagnostic to guide therapy and target to undermine chemotherapy resistance.
2016-08-05 | GSE81157 | GEO
Project description:Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer, but the development of cisplatin-resistance limits its anti-tumor effects. Previous studies have shown that cisplatin resistance in bladder cancer may be related to a variety of factors, such as changes in drug transport and metabolism, enhancement of DNA repair mechanisms, changes in cell cycle regulation, inhibition of apoptosis, and epigenetic modification. While, the mechanism of cisplatin resistance is still elusive.In this study, we first found that upregulated ITGB4 is correlated with poor prognosis after chemotherapy in bladder cancer. Next, we demonstrated ITGB4 plays a key role in regulating the sensitivity of bladder cancer to cisplatin therapy. Then, we found that ITGB4 reduced the sensitivity of bladder cancer to cisplatin by inhibiting p53-S15 site phosphorylation and promoting MDM2 binding to p53 to reduce p53 expression. In addition, we demonstrated that ITGB4 regulates the antitumor effects of MDM2 inhibitors combined with cisplatin therapy. Further, we found that ITGB4 was elevated in bladder cancer cisplatin-resistant cells, and the increase in ITGB4 was mediated by STAT3.The combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin in bladder cancer.In summary, we identified ITGB4 as a key molecule affecting cisplatin sensitivity in bladder cancer, and proposed a strategy of combining drugs with STAT3 inhibitors to increase cisplatin sensitivity in bladder cancer.
2024-06-07 | GSE268855 | GEO
Project description:Platinum-based chemotherapeutics are used in many combination regimens in cancer. Despite extensive use across diverse cancer types, there is room for improved efficacy and patient selection for treatment. Here, we use bladder cancer to address both issues. A multi-omic assessment of five human bladder cancer cell lines and their chemotherapy resistant derivatives, coupled with in vitro whole-genome CRISPR screens were used to define functional drivers of treatment resistance. We identified 46 genes that sensitized the resistant cell lines to cisplatin plus gemcitabine (GemCis), a standard combination therapy in bladder cancer. Most genes were involved with DNA damage and repair pathways, which have previously been associated with enhanced sensitivity to cisplatin. Evaluating expression of the 46 genes in the whole transcriptome and proteome data in parental and resistant lines identified the puromycin sensitive aminopeptidase, NPEPPS, as a novel hit. Depletion of NPEPPS resulted in sensitizing resistant bladder cancer cells to cisplatin in vitro and in xenograft experiments. Pharmacologic inhibition of NPEPPS with tosedostat in cells and in chemoresistant, bladder cancer patient-derived tumoroids improved response to cisplatin. Prior work found NPEPPS in a protein complex with volume regulated anion channels (VRACs) in several cell line models. Interestingly, depletion of two VRAC subunits, LRRC8A and LRRC8D, known importers of intracellular cisplatin, enhanced resistance to cisplatin. Our findings support NPEPPS as a novel and druggable driver of cisplatin resistance with the potential for rapid translation to clinical investigation.
2024-02-20 | PXD024742 | Pride
Project description:Platinum-based chemotherapeutics are used in many combination regimens in cancer. Despite extensive use across diverse cancer types, there is room for improved efficacy and patient selection for treatment. Here, we use bladder cancer to address both issues. A multi-omic assessment of five human bladder cancer cell lines and their chemotherapy resistant derivatives, coupled with in vitro whole-genome CRISPR screens were used to define functional drivers of treatment resistance. We identified 46 genes that sensitized the resistant cell lines to cisplatin plus gemcitabine (GemCis), a standard combination therapy in bladder cancer. Most genes were involved with DNA damage and repair pathways, which have previously been associated with enhanced sensitivity to cisplatin. Evaluating expression of the 46 genes in the whole transcriptome and proteome data in parental and resistant lines identified the puromycin sensitive aminopeptidase, NPEPPS, as a novel hit. Depletion of NPEPPS resulted in sensitizing resistant bladder cancer cells to cisplatin in vitro and in xenograft experiments. Pharmacologic inhibition of NPEPPS with tosedostat in cells and in chemoresistant, bladder cancer patient-derived tumoroids improved response to cisplatin. Prior work found NPEPPS in a protein complex with volume regulated anion channels (VRACs) in several cell line models. Interestingly, depletion of two VRAC subunits, LRRC8A and LRRC8D, known importers of intracellular cisplatin, enhanced resistance to cisplatin. Our findings support NPEPPS as a novel and druggable driver of cisplatin resistance with the potential for rapid translation to clinical investigation.
2023-12-31 | GSE179799 | GEO
Project description:Platinum-based chemotherapeutics are used in many combination regimens in cancer. Despite extensive use across diverse cancer types, there is room for improved efficacy and patient selection for treatment. Here, we use bladder cancer to address both issues. A multi-omic assessment of five human bladder cancer cell lines and their chemotherapy resistant derivatives, coupled with in vitro whole-genome CRISPR screens were used to define functional drivers of treatment resistance. We identified 46 genes that sensitized the resistant cell lines to cisplatin plus gemcitabine (GemCis), a standard combination therapy in bladder cancer. Most genes were involved with DNA damage and repair pathways, which have previously been associated with enhanced sensitivity to cisplatin. Evaluating expression of the 46 genes in the whole transcriptome and proteome data in parental and resistant lines identified the puromycin sensitive aminopeptidase, NPEPPS, as a novel hit. Depletion of NPEPPS resulted in sensitizing resistant bladder cancer cells to cisplatin in vitro and in xenograft experiments. Pharmacologic inhibition of NPEPPS with tosedostat in cells and in chemoresistant, bladder cancer patient-derived tumoroids improved response to cisplatin. Prior work found NPEPPS in a protein complex with volume regulated anion channels (VRACs) in several cell line models. Interestingly, depletion of two VRAC subunits, LRRC8A and LRRC8D, known importers of intracellular cisplatin, enhanced resistance to cisplatin. Our findings support NPEPPS as a novel and druggable driver of cisplatin resistance with the potential for rapid translation to clinical investigation.
2023-12-31 | GSE171537 | GEO
Project description:Cisplatin-based chemotherapy is the standard care regimen in bladder cancer (BC). However, resistance to the therapy whose molecular mechanisms of the resistance are not fully elucidated rapidly develops in BC patients. Here we introduced multidimensional proteomic analysis providing different levels of protein information, which included global proteome and phosphorpoteome perturbed by EGF using the cisplatin resistant BC model. Integrated analysis of protein expression and phosphorylation provided comprehensive profiles of altered proteins in cisplatin resistant cells that are dependent and independent on EGF, as well as suggesting significance of protein phosphorylation in resistance mechanisms in BC. From the reconstruction of cisplatin resistance associated network model and subsequent kinase enrichment analysis, we have identified three key kinases, CDK2, CHEK1, and ERBB2 as central regulators mediating cisplatin resistance. Experimental validation showed phosphorylation events in these central kinases and their putative substrates, suggesting evidence that activation of three kinases are important to acquired resistance to cisplatin in BC. Expanded analysis with this proteomic discovery to transcriptome profiles from BC cohorts nominated the 7 gene panel associated with poor survival after cisplatin-based chemotherapy. These findings provide insightful strategies to classify high-risk BC patients upon current chemotherapies and to identify therapeutic targets for recurrence disease.
2020-05-26 | PXD005308 | Pride
Project description: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.
2024-04-10 | GSE217413 | GEO
Project description:Cisplatin-based chemotherapy is the most common treatment for unresectable bladder cancers and also increasingly used as neoadjuvant treatments before or after surgery and radiotherapy. Unfortunately, though many patients respond to the treatment, most of them develop resistance quickly with unclear mechanisms and few further treatment options. Here, we report that semi-squamazation is acquired during chemo treatment in both mice and human. Multi-omics analyses show that cathepsin H (CTSH), a direct target of p63, is associated with chemoresistance and semi-squamation. Treatment with the cathepsin inhibitor E64 specifically restrains chemoresistant but not chemosensitive cancer. Mechanistically, cathepsin inhibition induces fully squamous differentiation of bladder cancer cells, which requires TNF receptor 1alpha and is associated with pyroptosis. Our study suggests that semi-squamazation would be a diagnosistic marker for chemoresistance and differentiation therapy by targeting CTSH might be a potential treatment for chemoresistant bladder cancer.
2022-07-09 | GSE192575 | GEO
Project description:SCLC is the most aggressive subtype of lung cancer characterized by a remarkable response to chemotherapy followed by development of resistance. Mechanisms of initial sensitivity and of subsequent resistance are not understood. Here we highlight a broad tumor heterogeneity in mouse models of SCLC, which includes a CDH1 high primary cisplatin-resistant peripheral neuroendocrine lesion with unique metabolic and structural profile. Cisplatin treatment preferentially eliminates CDH1 negative secondary tumor leaving behind CDH1 high primary lesions, thus revealing a striking differential response. We profile global protein and messenger RNA levels in vehicle and cisplatin treated lung tumor populations and find a marked reduction in proliferation and a pronounced metabolic shift following cisplatin-treatment. Our proteo-transcriptomic analysis gives insight into gene expression alterations that characterize cisplatin resistance and uncovers potential novel targets to overcome resistance of distinct populations. SCLC tumors in the mouse show heterogeneity which appears, as might be the case in humans, to be one of the underlying mechanisms of differential sensitivity to cisplatin.
2019-11-12 | PXD010680 | Pride