Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

C-Met activation leads to the establishment of a TGFβ receptor regulatory network required for bladder cancer invasion

ABSTRACT: Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the precise mechanisms underlying HGF/c-MET mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to the E3 ligase SMURF2 targeting the TGFβ receptor for degradation. Under these conditions SMAD7 acts as an agonist disrupting the intermolecular interactions within SMURF2, permitting SMURF2 activation. We demonstrate that HGF stimulates TGFβ signaling by inducing c-SRC mediated phosphorylation of SMURF2 at two tyrosine residues impeding SMAD7 binding and enhancing SMURF2 C2-HECT domain interaction, resulting in SMURF2 inhibition and TGFβ receptor stabilization. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. Using biologically relevant orthotopic mouse models we show that inhibition of TGFβ signaling completely prevents HGF induced bladder cancer invasion. Furthermore, we make a rationale for the use of TGFβ receptor and MEK inhibitors in the treatment of high grade non-muscle-invasive bladder cancers or early stage muscle invasive bladder cancers.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Kidney

DISEASE(S): Urinary Bladder Cancer

SUBMITTER: Dennis Kappei

LAB HEAD: Dennis Kappei

PROVIDER: PXD014736 | Pride | 2019-08-26

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	20151116_QPC_DK_CSI_Eichhorn_Scr_for.raw	Raw
	20151116_QPC_DK_CSI_Eichhorn_Scr_rev.raw	Raw
	SMURF2_txt.zip	Other

Items per page:

1 - 3 of 3

Similar Datasets

c-Met activation leads to the establishment of a TGFb regulatory network required for bladder cancer invasion

Project description:Aberrant c-Met activation and upregulation of its cognate ligand HGF are frequently observed in bladder cancer and have been shown to regulate downstream pathways involved in proliferation, motility, and invasion. The precise mechanism underlying HGF/c-MET mediated invasion in bladder cancer is partly addressed by this microarray dataset. HGF activates the canonical TGFb signaling pathway to enhance epithelial mesenchymal transition and bladder carcinoma invasion.

2019-08-23 | GSE104740 | GEO

Whole genome expression data from human urinary bladder cancer

Project description:At diagnosis approximately 75% of bladder urothelial carcinomas are non muscle invasive bladder cancers (Ta, T1 and Tis), 20% are muscle invasive bladder cancer (T2-T4) and 5% are already metastatic. Non muscle invasive bladder cancers are characterized by tumor recurrence in 60% to 85% of cases and, therefore, long-term followup is needed. The current standard methods to detect and monitor bladder cancer are cystoscopy and cytology. Cystoscopy is an invasive method and cytology is hampered by low sensitivity, especially for low grade tumors. So there is need to develop reliable and noninvasive methods to detect and predict bladder cancer biological behavior. So we have performed high density oligonucleotide microarray for discovery of new molecular markers to diagnose and predict the outcome of bladder cancer. Under an ethical guideline of Chhatrapati Shahuji Maharaj Medical University, India histologically confirmed seven bladder cancer patients were recruited from Department of Urology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India. Total RNA was extracted from tumor biopsies and hybridized on affymetrix Human Gene ST 1.1 array to determine differentially expressed genes in urinary bladder cancer with muscle invasion in comparison of normal human urinary bladder.

2012-02-22 | E-GEOD-23732 | biostudies-arrayexpress

Identification of subsets of urothelial carcinoma

Project description:Identification of bladder cancer subsets 142 primary bladder tumors including superficial and invasive tumors were arrayed. 73 invasive tumors out of 142 tumors were used for muscle invasive baldder cancer classification

2014-02-10 | E-GEOD-48075 | biostudies-arrayexpress

Bladder cancer expression profiling

Project description:Cystoscopic bladder biopsies were obtained from 19 patients and 11 controls between 2004 and 2005. Whole transcript based arrays were used to identify differences in expression profile between cancer and normal, muscle-invasive or non-muscle invasive cancer and normal, grade 1 and grade 3 bladder cancer.

2014-07-01 | E-MTAB-1560 | biostudies-arrayexpress

Whole genome expression data from human urinary bladder cancer

2012-02-22 | GSE23732 | GEO

Effect of EZH2 inhibition on ARID1A mutant bladder cancer cell lines

Project description:ARID1A, a subunit of SWI/SNF chromatin remodeling complex. SWI/SNF complex can regulate expression of genes involved in vital biological processes such as cell cycle, DNA damage repair and development. ARID1A is known to have high mutation rate in human cancers including bladder cancer, leading to its loss of function. Publicly available whole exome sequencing data for muscle invasive and non-muscle invasive bladder cancers, show fraction of tumors with truncated ARID1A. Thus identifying therapeutic strategies for ARID1A mutant cancers is of high importance. EZH2, a histone methyltransferase is known to over-express and play pivotal role in aggressive bladder cancer. Our preliminary studies show that treatment of EZH2 inhibitor (GSK126) on ARID1A mutant bladder cancer cells significantly reduced cancer cell viability, invasion and colony formation relative to wild type ARID1A containing cells. Here, we performed microarray experiments to assess the effect of EZH2 inhibitor on global transcriptome of both ARID1A mutant and wild type bladder cancer cell line.

2023-05-01 | GSE150249 | GEO

FLI1 and FRA1 transcription factors drive the transcriptional regulatory networks characterizing muscle invasive bladder cancer

Project description:Identification of transcriptional regulatory networks in muscle invasive and non-muscle invasive bladder cancer cell lines

2023-02-17 | PXD028665 | Pride

Loss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladder [RIP-seq]

Project description:Bladder cancer poses significant clinical challenges due to its high metastatic potential and poor prognosis, especially when it progresses to muscle-invasive stages. Here, we show that the m6A reader YTHDC1 is downregulated in muscle-invasive bladder cancer and is negatively correlated with the expression of epithelial‒mesenchymal transition genes. The functional inhibition or depletion of YTHDC1 increased the migration and invasion of urothelial cells. Integrative analysis of multimodal sequencing datasets provided detailed insights into the molecular mechanisms mediating YTHDC1-dependent phenotypes and identified SMAD6 as a key transcript involved in the invasiveness of urothelial carcinoma of the bladder. Notably, SMAD6 mRNA colocalized less with YTHDC1 in tumoral tissues than in paratumoral tissues, indicating disrupted binding during cancer progression. Our findings establish YTHDC1-dependent m6A reading as a critical epitranscriptomic mechanism regulating bladder cancer invasiveness and provide a paradigm for the epitranscriptomic deregulation of cancer-associated networks.

2024-12-16 | GSE266224 | GEO

Loss of YTHDC1 m6A reading function promotes invasiveness in urothelial carcinoma of the bladder [RNA-seq]

2024-12-16 | GSE266223 | GEO

RNA-sequencing of Non-muscle Invasive Bladder cancer (NMIBC)

Project description:This RNA-sequencing cohort includes 52 Non-muscle Invasive Bladder cancer (NMIBC) samples and 6 Muscle Invasive Bladder cancer (MIBC) samples.

| EGAS00001004358 | EGA