Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Therapeutic and prognostic implications of NOTCH and MAPK signaling in bladder cancer.

ABSTRACT: Signaling pathways that drive bladder cancer (BC) progression may be promising and specific targets for systemic therapy. Here, we investigated the clinical significance and targetability of NOTCH and mitogen-activated protein kinase (MAPK) signaling for this aggressive malignancy. We assessed NOTCH1 and MAPK activity in 222 stage III and IV BC specimens of patients that had undergone radical cystectomy, and tested for clinical associations including cancer-specific and overall survival. We examined therapeutic effects of NOTCH and MAPK repression in a murine xenograft model of human bladder cancer cells and evaluated tumor growth and tumor cell plasticity. In BC, NOTCH1 and MAPK signaling marked two distinct tumor cell subpopulations. The combination of high NOTCH1 and high MAPK activity indicated poor cancer-specific and overall survival in univariate and multivariate analyses. Inhibition of NOTCH and MAPK in BC xenografts in vivo depleted targeted tumor cell subpopulations and revealed strong plasticity in signaling pathway activity. Combinatorial inhibition of NOTCH and MAPK signaling most strongly suppressed tumor growth. Our findings indicate that tumor cell subpopulations with high NOTCH and MAPK activity both contribute to tumor progression. Furthermore, we propose a new concept for BC therapy, which advocates specific and simultaneous targeting of these different tumor cell subpopulations through combined NOTCH and MAPK inhibition.

SUBMITTER: Schulz GB

PROVIDER: S-EPMC8088911 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

SEC23A Is an Independent Prognostic Biomarker in Bladder Cancer Correlated With MAPK Signaling.

Project description:Clinical data mining and bioinformatics analysis can be employed effectively to elucidate the function and underlying mechanisms of the gene of interest. Here, we have proposed a framework for the identification and validation of independent biomarkers in human cancer and for mechanistic profiling using gene sets enrichment analysis and pathway analysis. This is followed by validation with in vitro experiments. Using this framework to analyze the clinical relevance of SEC23A, we have discovered the prognostic potential of SEC23A in different cancers and identified SEC23A as an independent prognostic factor for poor prognosis in bladder cancer, which implicates SEC23A, for the first time, as an oncogene. Bioinformatic analyses have elucidated an association between SEC23A expression and the upregulation of the MAPK signaling pathway. Using the T24 human bladder cell line, we confirmed that knockdown of SEC23A expression could effectively impact the MAPK signaling pathway. Further, through PCR verification, we showed that MEF2A, one of the key genes of the MAPK signaling pathway, might be a downstream factor of the SEC23A gene.

| S-EPMC8385657 | biostudies-literature

Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer.

Project description:Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and cross-talk with other signaling pathways. The canonical Notch pathway with four Notch receptors (Notch1-4) and five ligands (DLL1, 3-4, Jagged 1-2) is an evolutionarily conserved cell signaling pathway that plays critical roles in cell-fate determination, differentiation, development, tissue patterning, cell proliferation, and death. In cancer, these roles have a critical impact on tumor behavior and response to therapy. Because the role of Notch remains tissue and context dependent, alterations within this pathway may lead to tumor suppressive or oncogenic phenotypes. Although no FDA-approved therapies currently exist for the Notch pathway, multiple therapeutics (e.g., demcizumab, tarextumab, GSI MK-0752, R04929097, and PF63084014) have been developed to target different aspects of this pathway for both hematologic and solid malignancies. Understanding the context-specific effects of the Notch pathway will be important for individualized therapies targeting this pathway.

| S-EPMC4333206 | biostudies-literature

Epigenetically regulated gene expression profiles recognized three molecular classifications with prognostic and therapeutic implications in bladder cancer.

Project description: Not available

| S-EPMC9982075 | biostudies-literature

Genomic Landscape of Young-Onset Bladder Cancer and Its Prognostic Implications on Adult Bladder Cancer.

Project description:Due to the rare occurrence of young-onset bladder cancer (YBC), its genomic characteristics remain largely unknown. Twenty-nine biopsy-proven YBC cases were collected using a nation-wide search for bladder cancer diagnosed at 20 years or younger. Whole exome sequencing and RNA sequencing were carried out in 21 and 11 cases, respectively, and compared with those of adult bladder cancer (ABC) cases obtained from public databases. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had a low mutation burden and less complex copy number alterations. All cases harbored putative driver mutations. Mutations were most commonly found in HRAS (10 cases), with a preference for exon 5. FGFR3 gene fusions were noted with various partner genes (7 cases). The alterations on HRAS and FGFR3 occurred in a mutually exclusive manner. Others included KRAS mutations (2 cases), chromosomes 4p and 10q arm-level deletions (1 case), and ERCC2 mutation (1 case). There were no point mutations in TP53 and FGFR3. The gene expression profiles of YBC were similar to those of the ABC group with good prognosis. None of the YBCs and ABCs with YBC-like mutations showed progression to muscle-invasive tumors. Our results suggest that bladder cancer with YBC-like mutations represents an indolent bladder tumor, regardless of age.

| S-EPMC7073191 | biostudies-literature

Laminin-integrin a6b4 interaction activates notch signaling to facilitate bladder cancer development.

Project description:BackgroundLaminins are high-molecular weight (400 ~ 900 kDa) proteins in extracellular matrix, which serve as major component of the basal lamina, and play a crucial role in promoting tumor cell migration. This study aimed at characterizing the role of laminin in promoting cancer development, and elucidating the mechanism of tumor progression driven by laminin-Notch signaling in bladder cancer.Methods2D collagen/laminin culture system was established and CCK-8/transwell assay was conducted to evaluate the proliferation/migration ability of Biu-87 and MB49 cells cultured on 2D gels. Activation of integrins-Notch1 signaling was determined by western blotting. Orthotopic bladder cancer mice model was established to assess the therapeutic effects of Notch inhibitor.ResultsOur study demonstrated that extracellular laminin can trigger tumor cell proliferation/migration through integrin α6β4/Notch1 signaling in bladder cancer. Inhibition of Telomere repeat-binding factor 3 (TRB3)/Jagged Canonical Notch Ligand 1 (JAG1) signaling suppressed Notch signals activation induced by laminin-integrin axis. In MB49 orthotopic bladder cancer mice model, Notch inhibitor SAHM1 efficiently improved tumor suppressive effects of chemotherapy and prolonged survival time of tumor-bearing mice.ConclusionIn conclusion, we show that, in bladder cancer, extracellular laminin induced the activation of Notch pathway through integrin α6β4/TRB3/JAG3, and disclosed a novel role of laminin in bladder cancer cells proliferation or migration.

| S-EPMC9118635 | biostudies-literature

Notch pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation.

Project description:Mutually exclusive genetic alterations in the RET, RAS, or BRAF genes, which result in constitutively active mitogen-activated protein kinase (MAPK) signaling, are present in about 70% of papillary thyroid carcinomas (PTCs). However, the effect of MAPK activation on other signaling pathways involved in oncogenic transformation, such as Notch, remains unclear. In this study, we tested the hypothesis that the MAPK pathway regulates Notch signaling and that Notch signaling plays a role in PTC cell proliferation. Conditional induction of MAPK signaling oncogenes RET/PTC3 or BRAF(T1799A) in normal rat thyroid cell line mediated activation of Notch signaling, upregulating Notch1 receptor and Hes1, the downstream effector of Notch pathway. Conversely, pharmacological inhibition of MAPK reduced Notch signaling in PTC cell. Thyroid tumor samples from transgenic mice expressing BRAF(T1799A) and primary human PTC samples showed high levels of Notch1 expression. Down-regulation of Notch signaling by ?-secretase inhibitor (GSI) or NOTCH1 RNA interference reduces PTC cell proliferation. Moreover, the combination of GSI with a MAPK inhibitor enhanced the growth suppression in PTC cells. This study revealed that RET/PTC and BRAF(T1799A) activate Notch signaling and promote tumor growth in thyroid follicular cell. Taken together, these data suggest that Notch signaling may be explored as an adjuvant therapy for thyroid papillary cancer.

| S-EPMC3610552 | biostudies-literature

Therapeutic Targeting of Notch Signaling: From Cancer to Inflammatory Disorders.

Project description:Over the past two decades, the Notch signaling pathway has been investigated as a therapeutic target for the treatment of cancers, and more recently in the context of immune and inflammatory disorders. Notch is an evolutionary conserved pathway found in all metazoans that is critical for proper embryonic development and for the postnatal maintenance of selected tissues. Through cell-to-cell contacts, Notch orchestrates cell fate decisions and differentiation in non-hematopoietic and hematopoietic cell types, regulates immune cell development, and is integral to shaping the amplitude as well as the quality of different types of immune responses. Depriving some cancer types of Notch signals has been shown in preclinical studies to stunt tumor growth, consistent with an oncogenic function of Notch signaling. In addition, therapeutically antagonizing Notch signals showed preclinical potential to prevent or reverse inflammatory disorders, including autoimmune diseases, allergic inflammation and immune complications of life-saving procedures such allogeneic bone marrow and solid organ transplantation (graft-versus-host disease and graft rejection). In this review, we discuss some of these unique approaches, along with the successes and challenges encountered so far to target Notch signaling in preclinical and early clinical studies. Our goal is to emphasize lessons learned to provide guidance about emerging strategies of Notch-based therapeutics that could be deployed safely and efficiently in patients with immune and inflammatory disorders.

| S-EPMC8194077 | biostudies-literature

Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer.

Project description:The carbonic anhydrases (CAs) comprise a family of evolutionarily ancient enzymes found ubiquitously in nature. They have important roles in facilitating transport of carbon dioxide and protons in the intracellular space, across biological membranes and in the unstirred layers of the extracellular space. The tumour-associated isoenzymes, CAIX and CAXII, are expressed in a wide variety of malignancies and appear to be tightly regulated by microenvironmental hypoxia. CAIX expression is linked to poor prognosis in a number of human tumours, and may be a marker of aggressive malignant phenotype and a mechanism of progression. Inhibitors of CA may inhibit tumour growth and invasion, with consequent therapeutic potential.

| S-EPMC2394207 | biostudies-other

HnRNP-L mediates bladder cancer progression by inhibiting apoptotic signaling and enhancing MAPK signaling pathways.

Project description:Heterogeneous nuclear ribonucleoprotein L (hnRNP-L) is a promoter of various kinds of cancers, but its actions in bladder cancer (BC) are unclear. In this study, we investigated the function and the underlying mechanism of hnRNP-L in bladder carcinogenesis. Our results demonstrated that enhanced hnRNP-L expression in BC tissues was associated with poor overall survival of BC patients. Depletion of hnRNP-L significantly suppressed cell proliferation in vitro and inhibited xenograft tumor growth in vivo. Furthermore, downregulation of hnRNP-L resulted in G1-phase cell cycle arrest and enhanced apoptosis accompanied by inhibition of EMT and cell migration. All these cellular changes were reversed by ectopic expression of hnRNP-L. Deletion of hnRNP-L resulted in decreased expression of Bcl-2, enhanced expression of caspases-3, -6 and -9 and inhibition of the MAPK signaling pathway. These findings demonstrate that hnRNP-L contributes to poor prognosis and tumor progression of BC by inhibiting the intrinsic apoptotic signaling and enhancing MAPK signaling pathways.

| S-EPMC5355122 | biostudies-literature

Prognostic Implications of Immune-Related Gene Pairs Signatures in Bladder Cancer.

Project description:Compelling evidence indicates that immune function is correlated with the prognosis of bladder cancer (BC). Here, we aimed to develop a clinically translatable immune-related gene pairs (IRGPs) prognostic signature to estimate the overall survival (OS) of bladder cancer. From the 251 prognostic-related IRGPs, 37 prognostic-related IRGPs were identified using LASSO regression. We identified IRGPs with the potential to be prognostic markers. The established risk scores divided BC patients into high and low risk score groups, and the survival analysis showed that risk score was related to OS in the TCGA-training set (p < 0.001; HR = 7.5 [5.3, 10]). ROC curve analysis showed that the AUC for the 1-year, 3-year, and 5-year follow-up was 0.820, 0.883, and 0.879, respectively. The model was verified in the TCGA-testing set and external dataset GSE13507. Multivariate analysis showed that risk score was an independent prognostic predictor in patients with BC. In addition, significant differences were found in gene mutations, copy number variations, and gene expression levels in patients with BC between the high and low risk score groups. Gene set enrichment analysis showed that, in the high-risk score group, multiple immune-related pathways were inhibited, and multiple mesenchymal phenotype-related pathways were activated. Immune infiltration analysis revealed that immune cells associated with poor prognosis of BC were upregulated in the high-risk score group, whereas immune cells associated with a better prognosis of BC were downregulated in the high-risk score group. Other immunoregulatory genes were also differentially expressed between high and low risk score groups. A 37 IRGPs-based risk score signature is presented in this study. This signature can efficiently classify BC patients into high and low risk score groups. This signature can be exploited to select high-risk BC patients for more targeted treatment.

| S-EPMC8331311 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data