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Forkhead Box F1 acts as a novel prognostic biomarker and induces caspase-dependent apoptosis in bladder cancer

ABSTRACT: Down-regulated expression of Forkhead Box F1 (FOXF1) in malignant tumors were reported in several kinds of cancer before, but its role in bladder cancer (BC) was not clear. This study aims to demonstrate the prognostic value and of FOXF1 in BC patients. Here, a retrospectively recruited BC cohort and public datasets were utilized to identify the predictive ability of FOXF1 and its relationship between clinical information in BC patients. The expression level of FOXF1 is notably higher in BC tissues than para-cancerous mucosae. Low FOXF1 expression is correlated to unfavorable clinicopathological features and poor prognosis. Further, in bladder tumor cells, the expression levels of FOXF1 mRNA and protein were tested by quantitative real-time PCR and western blot. The viability of cells was examined by CCK-8, EdU, and clonogenic capacity assays. Cell apoptosis was detected by flow cytometry. We note that FOXF1 activating could impair cell viability and induce apoptosis in BC. Then, caspase 3 as a downstream gene of FOXF1 was spotted by RNA-Seq and PPI. The anti-tumor effect of FOXF1 were also validated in animal models. In conclusion, down-regulated FOXF1 expression is a potential independent indicator for unfavorable clinical outcomes of BC patients, FOXF1 inhibits BC cells proliferation and induces cell apoptosis via caspase signaling pathway. This study exhibits FOXF1 express pattern, demonstrates the prognostic predictive ability of FOXF1 and prove the anti-tumor mechanisms of FOXF1 in BC, it has reference value to clinical decision, activation FOXF1 expression could be used as a new strategy in tumor therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229810 | GEO | 2023/07/18

REPOSITORIES: GEO

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Identification of CDK1 phosphorylation of TFCP2L1 from murine embryonic stem cells and bladder cancer cells

Project description:Molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. However, their precise roles and regulatory mechanisms remain elusive. Here, we showed that CDK1 phosphorylation of TFCP2L1, a pluripotency-associated transcription factor, orchestrated pluripotency and cell-cycling in embryonic stem cells (ESCs) and was aberrantly activated in aggressive bladder cancers (BCs). In murine ESCs, the protein interactome and transcription targets of Tfcp2l1 indicated its involvement in cell-cycle regulation. Tfcp2l1 was phosphorylated at Thr177 by Cdk1, which affected ESC cell-cycle progression, pluripotency, and differentiation. LC-MS was used to characterize thr177 phosphorylation in TFCP2L1 protein obtained by IP experiment and kinase assay. The CDK1-TFCP2L1 pathway was activated in human BC cells, stimulating their proliferation, self-renewal, and invasion. Lack of TFCP2L1 phosphorylation impaired the tumorigenic potency of BC cells in a xenograft model. In patients with BC, high co-expression of TFCP2L1 and CDK1 was associated with unfavorable clinical characteristics including tumor grade, lymphovascular and muscularis propria invasion, and distant metastasis and was an independent prognostic factor for cancer specific survival. These findings demonstrate the molecular and clinical significance of CDK1-mediated TFCP2L1 phosphorylation in stem-cell pluripotency and in the tumorigenic stemness features associated with BC progression.

2019-11-08 | PXD015635 | Pride

Transcriptome profiling of T24 cells treated with Momordica Charantia MAP30

Project description:Bladder cancer (BC) is notably prevalent, particularly among men. Emerging evidence highlights that traditional Chinese medicine (TCM) has distinct anticancer properties. This study focuses on recombinant MAP30, a key active constituent of bitter melon extract, recognized for its antiviral, immunomodulatory, and antitumor effects. We discovered that MAP30 suppresses BC cell proliferation and induces apoptosis in a dose-responsive manner. It also hinders cell migration, as evidenced by Transwell and wound healing assays. In nude mice, MAP30 injections adjacent to tumors significantly curtail tumor growth. Molecular analyses after MAP30 exposure show elevated SA-β-Gal activity and increased expression of cell cycle inhibitors p21 and p16 in BC cells. Integrating TCGA BC data, MAP30 appears to correct dysregulated gene expression associated with the cell cycle, senescence, apoptosis, and key pathways such as FOXO, TNF, and MAPK. Proteomic analysis identifies CENPA as a central molecule inhibited by MAP30. Correlation studies reveal CENPA’s significant association with oncogenic and immune-modulatory gene expression and immune cell infiltration. CENPA knockdown diminishes BC cell growth and motility, while its overexpression in MAP30-treated cells reverses these effects, suggesting CENPA’s pivotal role in MAP30’s anticancer activity and its potential as a therapeutic target. In conclusion, recombinant MAP30 effectively hampers bladder cancer cell proliferation and migration via CENPA downregulation and induces apoptosis and senescence, offering therapeutic potential against bladder cancer.

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In vivo disruption of Rb-E2F-Ezh2 signaling loop causes bladder cancer development

Project description:Bladder cancer (BC) is a highly prevalent human disease in which Rb pathway inactivation and epigenetic alterations are common events. However, the connection between these two processes is still poorly understood. Here we show that the in vivo inactivation of all Rb family genes in the mouse urothelium is sufficient to initiate BC development. The characterization of the mouse tumors revealed multiple molecular features of human BC, including the activation of E2F transcription factor and subsequent Ezh2 expression, and the activation of several signaling pathways previously identified as highly relevant in urothelial tumors. Whole transcriptional characterizations of the mouse bladder tumors revealed a significant overlap with human BC samples, and a predominant role for Ezh2 in the downregulation of gene expression programs. Importantly, we determined that in human superficial BC patients, the increased tumor recurrence and progression in these recurrences is associated with increased E2F and Ezh2 expression and Ezh2-mediated gene expression repression. Collectively, our studies provide a genetically defined model for human high-grade superficial BC and demonstrate the existence of an Rb-E2F-Ezh2 axis in bladder whose disruption can promote tumor development. Gene expression was analyzed in normal bladder and bladder tumours, both in humans and in transgenic mice.

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Project description:Previous studies successfully revealed molecular characteristics of bladder cancers, dealing with non-muscle invasive bladder cancer and muscle invasive bladder cancer, separately. At the molecular level, however, there is a great need to aggregate these subtypes, which may share biological characteristics. This study aimed to identify distinct molecular subtypes of BC and the clinical and/or biological characteristics of each subtype. We used seven gene expression data sets for bladder cancer, which included data from 118 primary bladder cancer samples and 27 recurrent bladder tumor tissues from the Yonsei University Severance Hospital. Hierarchical clustering revealed four molecular subtypes of BC with different clinical outcomes: class 1 with low-grade NMIBC and the best prognosis; class 2 characterized by active FGFR3 and inhibited immune response pathways; class 3 with high-grade NMIBC and the worst progression-free survival; and class 4 mainly comprised of MIBC along with EMT activation. By applying the classifier based on these characteristics, we stratified all BC samples into newly identified molecular subtypes. When comparing previously reported subtypes, our subtypes well agreed with their molecular characteristics regardless of breast cancer-based biology, and showed a strong prognostic relevance in class 3. Integrative analysis of mutation and gene expression suggested that class 3 may have the potential benefit from anti-PD-L1 immunotherapy. Our classifier, constructed by NMIBC and MIBC integration, successfully stratified BC patients into distinct subtypes with different clinical outcomes and a possible treatment option.

2018-10-03 | GSE120736 | 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.

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Tumor-infiltrating lymphocytes, prognosis and trastuzumab benefit in early-stage breast cancer patients from the FinHER trial

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In vivo disruption of Rb-E2F-Ezh2 signaling loop causes bladder cancer development

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a phase 2 trial of DDMVAC and bevacizumab in urothelial cancer

Project description:A prognostic gene expression signature in chemotherapy-naïve bladder cancer is predictive of clinical outcomes from neoadjuvant chemotherapy

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PLD1 promotes tumor invasion by regulation of MMP-13 expression via phosphorylation of NF-kB in bladder cancer

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Project description:Alterations in the epigenetic machinery in both tumor and immune cells contribute to bladder cancer (BC) development, constituting a promising target as an alternative therapeutic option. Here, we have explored the effects of a novel histone deacetylase (HDAC) inhibitor CM-1758, alone or in combination with immune checkpoint inhibitors (ICI) in BC. We determined the antitumor effects of CM-1758 in various BC cell lines together with the induction of broad transcriptional changes, with focus on the epigenetic regulation of PD-L1. Using an immunocompetent syngeneic mouse model of metastatic BC, we studied the effects of CM-1758 alone or in combination with anti-PD-L1 not only on tumor cells, but also in the tumor microenvironment. In vitro, we found that CM-1758 has cytotoxic and cytostatic effects either by inducing apoptosis or cell cycle arrest in BC cells at low micromolar levels. PD-L1 is epigenetically regulated by histone acetylation marks and is induced after treatment with CM-1758. We also observed that treatment with CM-1758 led to an important delay in tumor growth and a higher CD8+ T cell tumor infiltration. Moreover, anti-PD-L1 alone or in combination with CM-1758 reprogramed macrophage differentiation towards a M1-like polarization state and increased of pro-inflammatory cytokines systemically, yielding potential further cooperative antitumor effects. Our results suggest the possibility of combining HDAC inhibitors with immunotherapies for the management of advanced metastatic BC.

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