Gene expression in muscle invasive and non-muscle invasive bladder cancer cell lines exposed to hypoxia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE302555 | GEO | 2025/09/03
REPOSITORIES: GEO
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Project description:Muscle-invasive bladder cancer (MIBC) is a prevalent disease that can be treated with radiotherapy, but has a poor prognosis. Radiation-induced extracellular matrix (ECM) remodelling and fibrosis can induce tumour resistance and recurrence, but have not been studied in MIBC. Here, we aimed to characterise the impact of radiation on the ECM composition of MIBC. Three MIBC cell lines (T24, UMUC3, J82) were treated with fractionated radiation. We used proteomics to analyse the ECM composition produced by surviving cancer cells and immunofluorescence to investigate changes in the morphology and number of ECM fibres. We evaluated the RNA expression of identified ECM proteins (FN1, COL5A1, COL1A1, TNF6AIP6, FLG) in one cystectomy (TCGA-BLCA, n=397) and two radiotherapy (BC2001, n=313; BCON, n=151) cohorts. There were 613 proteins affected by radiation (padj<0.05, fold change >2 or <-2), 68 of which were ECM-associated proteins. There was a general increase in proteases and protease regulators but heterogeneity across cell lines. Enrichment analysis showed ECM organisation was the primary pathway affected. Immunofluorescence confirmed radiation affected ECM structure, generally, reducing the number, length and width of fibres. Five ECM genes of interest were identified (COL1A1, COL5A2, FN1, FLG, TNFAIP6), constituting an ECM signature. High FN1, COL1A1, TNF6AIP6 mRNA levels and ECM signature scores were independent poor prognostic markers, while FLG mRNA expression independently predicted radiotherapy benefit in a meta-analysis (n=861). We found high COL1A1 expression levels predicted hypoxia-modifying treatment benefit. Prognostic significance of COL5A2, FN1 and the ECM signature was dependent on patients harbouring TP53-mutations. Radiation alters the composition and structure of the ECM produced by MIBC. As a proof-of-concept, we showed that radiation-affected ECM genes are independent prognostic and predictive markers of radiotherapy benefit in MIBC. Future studies should validate these radiation-induced ECM changes in clinical samples, and explore the role of FLG in radioresistance.
2025-07-23 | PXD066069 | Pride
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Project description:INTRODUCTION: Progressive muscle-invasive bladder cancer (MIBC) has more aggressive behavior than de novo MIBC. This study aimed to ascertain the differences in gene expression profiles between both MIBC groups and to identify prognostic biomarkers to improve the treatment in these patients. MATERIAL AND METHODS: Retrospective multicentre study in which 212 MIBC patients (104 progressive and 108 de novo) who underwent radical cystectomy in the Hospital Clinic (Barcelona) and Radboud UMC (Nijmegen) were included. Total RNA from formalin-fixed paraffin-embedded tissue samples was obtained. Gene expression profiles of 27,965 coding transcripts were determined in 26 patients using Illumina microarrays. Expression levels of 94 genes selected from microarray data and literature were studied by quantitative PCR in an independent series of 186 de novo and progressive MIBC patients. Survival analysis was performed with the Kaplan-Meier method. R-software and SPSSv23 were used for all calculations. RESULTS: A total of 480 genes were found differently expressed (FDR<0.01) between progressive and de novo MIBC samples. Differential expression of 23 out of the 94 genes selected was validated in an independent set of samples. Survival analysis showed that expression of eight genes were prognostic factors of BCR. CONCLUSION: De novo and progressive MIBC patients show different gene expression profiles. In addition, we have identified eight genes with prognostic value which may contribute to improve BC risk stratification and, consequently, to tailor treatment and surveillance strategies in these patients.
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Project description:Adipose tissue is a plentiful and easily accessible source of mesenchymal stem cells that have been shown to be multi potent and possibly have immuno suppressive capacity(Zuk, Zhu et al. 2002; McIntosh, Zvonic et al. 2006; Prichard, Reichert et al. 2008). Several studies have identified hypoxia and the molecular effector of reduced oxygen tension, HIF1α to be essential in the differentiation processes, stem cell proliferation and survival as well as in maintenance of stem cell characteristics (Lennon, Edmison et al. 2001; Goda, Ryan et al. 2003; Wang, Fermor et al. 2005; Lin, Lee et al. 2006; Malladi, Xu et al. 2007; Ohnishi, Yasuda et al. 2007). The fact that oxygen has a central role in cell development and metabolism makes the regulation of oxygen tension a valuable tool in the attempt of exploiting stem cells to their full potential. In the current study we investigate the transcriptional changes caused by two weeks of monolayer hypoxic expansion of human adipose tissue derived stem cells (ASCs). Application of the XVivo hypoxic workstation (BioSpherix, Redfield, NY) made it possible to conduct the expansion of six ASC lines at four different hypoxic conditions in parallel covering the range from mild (15% oxygen) to full hypoxic (1% oxygen) conditions. In this comprehensive investigation the Illumina bead microarray platform was employed to give a profound and new insight in the molecular changes effectuated by hypoxic expansion. The findings of this study demonstrate the significance of biologic variation in the transcriptional response to mild hypoxic expansion and display evidence that full hypoxic growth conditions at 1% oxygen tension selects for a more prolific cell population of reduced chondrogenic potential. Keywords: hypoxia response To investigate the transcriptional response to hypoxia, adipose tissue derived stem cells (ASCs) from six female individuals were cultured for 14 days at different oxygen tensions (ambient, 15%, 10%, 5% and 1%). Gene expression levels at each oxygen tension were compared to ambient conditions (Ambient oxygen tension) using Illumina Human-6 v2.0 microarrays.
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Project description:This a model from the article:
Hypoxia-dependent sequestration of an oxygen sensor by a widespread structural motif can shape the hypoxic response - a predictive kinetic model
Bernhard Schmierer, Béla Novák1 and Christopher J Schofield
BMC Systems Biology2010, 4:139
20955552,
Abstract:
Background
The activity of the heterodimeric transcription factor hypoxia inducible factor (HIF) is regulated by the post-translational, oxygen-dependent hydroxylation of its α-subunit by members of the prolyl hydroxylase domain (PHD or EGLN)-family and by factor inhibiting HIF (FIH). PHD-dependent hydroxylation targets HIFα for rapid proteasomal degradation; FIH-catalysed asparaginyl-hydroxylation of the C-terminal transactivation domain (CAD) of HIFα suppresses the CAD-dependent subset of the extensive transcriptional responses induced by HIF. FIH can also hydroxylate ankyrin-repeat domain (ARD) proteins, a large group of proteins which are functionally unrelated but share common structural features. Competition by ARD proteins for FIH is hypothesised to affect FIH activity towards HIFα; however the extent of this competition and its effect on the HIF-dependent hypoxic response are unknown.
Results
To analyse if and in which way the FIH/ARD protein interaction affects HIF-activity, we created a rate equation model. Our model predicts that an oxygen-regulated sequestration of FIH by ARD proteins significantly shapes the input/output characteristics of the HIF system. The FIH/ARD protein interaction is predicted to create an oxygen threshold for HIFα CAD-hydroxylation and to significantly sharpen the signal/response curves, which not only focuses HIFα CAD-hydroxylation into a defined range of oxygen tensions, but also makes the response ultrasensitive to varying oxygen tensions. Our model further suggests that the hydroxylation status of the ARD protein pool can encode the strength and the duration of a hypoxic episode, which may allow cells to memorise these features for a certain time period after reoxygenation.
Conclusions
The FIH/ARD protein interaction has the potential to contribute to oxygen-range finding, can sensitise the response to changes in oxygen levels, and can provide a memory of the strength and the duration of a hypoxic episode. These emergent properties are predicted to significantly shape the characteristics of HIF activity in animal cells. We argue that the FIH/ARD interaction should be taken into account in studies of the effect of pharmacological inhibition of the HIF-hydroxylases and propose that the interaction of a signalling sensor with a large group of proteins might be a general mechanism for the regulation of signalling pathways.
There are there models described in the paper. 1) Skeleton Model 1 (SKM1) - HIFα CAD-hydroxylation in the absence of the FIH/AR-interaction. 2) Skeleton Model 2 (SKM2) - FIG sequestration by ARD proteins and oxygen-dependent FIH-release. 3) Full Model (Fusion of SKM1 and SKM2) - the effects of the FIH/ARD proteins interaction on HIFα CAD-hydroxylation.
This model corresponds to the "Full Model" described in the paper. The model reproduces figure 5 of the publication.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000300 | BioModels