Browse
Submit Data
Databases
API
Help

Dataset Information

29 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ROR1 is upregulated in endometrial cancer and represents a novel therapeutic target.

ABSTRACT: ROR1 and ROR2 are receptor tyrosine kinases with altered expression in a range of cancers. Silencing ROR1 or ROR2 in different tumour types has been shown to inhibit proliferation and decrease metastatic potential. The aim of this study was to investigate the role of ROR1 and ROR2 in endometrial cancer via immunohistochemistry (IHC) in a large endometrial cancer patient cohort (n = 499) and through in vitro analysis in endometrial cancer cell lines. Correlation was assessed between ROR1/2 expression and clinicopathological parameters. Kaplan Meier curves were produced for 5-year progression free survival (PFS) and overall survival (OS) with low/moderate versus high ROR1/2 intensity. Cox multivariate regression was applied to analyse the effect of selected covariates on the PFS and OS. The effect of ROR1 and/or ROR2 modulation on cell proliferation, adhesion, migration and invasion was analysed in two endometrial cancer cell lines (KLE and MFE-296). We observed a significant decrease in OS and PFS in patients with high ROR1 expression. ROR1 silencing and ROR2 overexpression significantly inhibited proliferation of KLE endometrial cancer cells and decreased migration. This study supports the oncogenic role of ROR1 in endometrial cancer, and warrants investigation of future application of ROR1-targeting therapies in endometrial cancer patients.

SUBMITTER: Liu D

PROVIDER: S-EPMC7431863 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Acid ceramidase is upregulated in AML and represents a novel therapeutic target.

Project description:There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Sphingolipid dysregulation through decreased ceramide levels and elevated sphingosine 1-phosphate (S1P) promotes cancer cell growth and survival. Acid ceramidase (AC) catalyzes ceramide breakdown to sphingosine, the precursor for S1P. We report for the first time that AC is required for AML blast survival. Transcriptome analysis and enzymatic assay show that primary AML cells have high levels of AC expression and activity. Treatment of patient samples and cell lines with AC inhibitor LCL204 reduced viability and induced apoptosis. AC overexpression increased the expression of anti-apoptotic Mcl-1, significantly increased S1P and decreased ceramide. Conversely, LCL204 induced ceramide accumulation and decreased Mcl-1 through post-translational mechanisms. LCL204 treatment significantly increased overall survival of C57BL/6 mice engrafted with leukemic C1498 cells and significantly decreased leukemic burden in NSG mice engrafted with primary human AML cells. Collectively, these studies demonstrate that AC plays a critical role in AML survival through regulation of both sphingolipid levels and Mcl-1. We propose that AC warrants further exploration as a novel therapeutic target in AML.

| S-EPMC5347763 | biostudies-literature

EMP2 is a novel therapeutic target for endometrial cancer stem cells.

Project description:Previous studies have suggested that overexpression of the oncogenic protein epithelial membrane protein-2 (EMP2) correlates with endometrial carcinoma progression and ultimately poor survival from disease. To understand the role of EMP2 in the etiology of disease, gene analysis was performed to show transcripts that are reciprocally regulated by EMP2 levels. In particular, EMP2 expression correlates with and helps regulate the expression of several cancer stem cell associated markers including aldehyde dehydrogenase 1 (ALDH1). ALDH expression significantly promotes tumor initiation and correlates with the levels of EMP2 expression in both patient samples and tumor cell lines. As therapy against cancer stem cells in endometrial cancer is lacking, the ability of anti-EMP2 IgG1 therapy to reduce primary and secondary tumor formation using xenograft HEC1A models was determined. Anti-EMP2 IgG1 reduced the expression and activity of ALDH and correspondingly reduced both primary and secondary tumor load. Our results collectively suggest that anti-EMP2 therapy may be a novel method of reducing endometrial cancer stem cells.

| S-EPMC5648618 | biostudies-literature

LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer.

Project description:Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC50 in the range of 20-100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.

| S-EPMC8367961 | biostudies-literature

Ribonucleotide reductase represents a novel therapeutic target in primary effusion lymphoma.

Project description:Primary effusion lymphoma (PEL) is a highly aggressive B-cell malignancy that is closely associated with one of oncogenic viruses infection, Kaposi's sarcoma-associated herpesvirus. PEL prognosis is poor and patients barely survive >6 months even following active chemotherapy interventions. There is therefore an urgent need to discover more effective targets for PEL management. We recently found that the ribonucleotide reductase (RR) subunit M2 is potentially regulated by the key oncogenic hepatocyte growth factor/c-MET pathway in PEL. In this study, we set to investigate the role of RR in PEL pathogenesis and to evaluate its potential as a therapeutic target. We report that the RR inhibitor 3-AP actively induces PEL cell cycle arrest through inhibiting the activity of the nuclear factor-?B pathway. Using a xenograft model, we found that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) effectively suppresses PEL progression in immunodeficient mice. Transcriptome analysis of 3-AP-treated PEL cell lines reveals altered cellular genes, most of whose roles in PEL have not yet been reported. Taken together, we propose that RR and its signaling pathway may serve as novel actionable targets for PEL management.

| S-EPMC5578886 | biostudies-literature

Aurora kinase A is upregulated in cutaneous T-cell lymphoma and represents a potential therapeutic target

Project description:Cutaneous T-cell lymphomas form a heterogeneous group of non-Hodgkin lymphomas characterized by only poor prognosis in advanced stage. Despite significant progress made in the identification of novel genes and pathways involved in the pathogenesis of cutaneous lymphoma, the therapeutic value of these findings has still to be proven. Here, we demonstrate by gene expression arrays that aurora kinase A is one of highly overexpressed genes of the serine/threonine kinase in CTCL. The finding was confirmed by qualitative RT-PCR, Western blotting and immunohistochemistry in CTCL cell lines and primary patient samples. Moreover, treatment with a specific aurora kinase A inhibitor blocks cell proliferation by inducing cell cycle arrest in G2 phase as well as apoptosis in CTCL cell lines. These new data provide a promising rationale for using aurora kinase A inhibition as a therapeutic modality of CTCL. 14 lesional skin biopsies of different MF patients (patch=3, plaque=6, tumor=4) and 9 healthy controls. Comparison between Cutaneus Tcell Lymphoma Samples and Healthy Control Tissue

2015-03-31 | E-GEOD-59307 | biostudies-arrayexpress

Anti-ROR1 scFv-EndoG as a Novel Anti-Cancer Therapeutic Drug

Project description:Aim: Immunotoxins are proteins that consist of an antibody fragment linked to a toxin, used as agents for targeted

| S-EPMC5844643 | biostudies-literature

MicroRNA-3613-3p functions as a tumor suppressor and represents a novel therapeutic target in breast cancer.

Project description:BackgroundMicroRNAs have been reported to participate in tumorigenesis, treatment resistance, and tumor metastasis. Novel microRNAs need to be identified and investigated to guide the clinical prognosis or therapy for breast cancer.MethodThe copy number variations (CNVs) of MIR3613 from Cancer Genome Atlas (TCGA) or Cancer Cell Line Encyclopedia (CCLE) were analyzed, and its correlation with breast cancer subtypes or prognosis was investigated. The expression level of miR-3613-3p in tumor tissues or serum of breast cancer patients was detected using in situ hybridization and qPCR. Gain-of-function studies were performed to determine the regulatory role of miR-3613-3p on proliferation, apoptosis, and tumor sphere formation of human breast cancer cells MDA-MB-231 or MCF-7. The effects of miR-3613-3p on tumor growth or metastasis in an immunocompromised mouse model of MDA-MB-231-luciferase were explored by intratumor injection of miR-3613-3p analogue. The target genes, interactive lncRNAs, and related signaling pathways of miR-3613-3p were identified by bioinformatic prediction and 3'-UTR assays.ResultsWe found that MIR3613 was frequently deleted in breast cancer genome and its deletion was correlated with the molecular typing, and an unfavorable prognosis in estrogen receptor-positive patients. MiR-3613-3p level was also dramatically lower in tumor tissues or serum of breast cancer patients. Gain-of-function studies revealed that miR-3613-3p could suppress proliferation and sphere formation and promote apoptosis in vitro and impeded tumor growth and metastasis in vivo. Additionally, miR-3613-3p might regulate cell cycle by targeting SMS, PAFAH1B2, or PDK3 to restrain tumor progression.ConclusionOur findings indicate a suppressive role of miR-3613-3p in breast cancer progression, which may provide an innovative marker or treatment for breast cancer patients.

| S-EPMC7836180 | biostudies-literature

Aurora kinase A is upregulated in cutaneous T-cell lymphoma and represents a potential therapeutic target

2015-03-31 | GSE59307 | GEO

ROR1 as a novel therapeutic target for EGFR-mutant non-small-cell lung cancer patients with the EGFR T790M mutation.

Project description:BackgroundActivation of bypass signaling pathways, impairment of apoptosis and mutation of epidermal growth factor receptor (EGFR) to a drug-resistant state are well known mechanisms of resistance to single-agent erlotinib therapy in non-small-cell lung cancer (NSCLC) driven by EGFR mutations. Orphan receptor 1 (ROR1) knockdown inhibited the growth of NCI-H1975 cells (harboring EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling in cooperation with AKT has been demonstrated.MethodsWe have assessed ROR1 expression in 45 patients from the EURTAC trial (clinicaltrials.gov NCT00446225), 27 of whom harbored pretreatment concomitant EGFR T790M mutations, and correlated results with outcome.ResultsProgression-free survival (PFS) was 11.8 months for erlotinib-treated patients with low/intermediate and 5.8 months for those with high ROR1 levels. PFS for chemotherapy-treated patients was 5.6 and 9 months, respectively (P=0.0165). A total of 15 erlotinib-treated patients harbored concomitant T790M mutations; for these patients, PFS was 10.8 months for those with low/intermediate compared to 2.7 months for those with high ROR1 levels. In contrast, among 12 chemotherapy-treated patients with concomitant T790M mutations, PFS was 5.8 months for those with low/intermediate, compared to 14.2 months for those with high ROR1 levels (P=0.0138).ConclusionsROR1 expression has a differential effect on outcome to erlotinib and chemotherapy in EGFR-mutant NSCLC patients. High ROR1 expression significantly limits PFS in erlotinib-treated patients with T790M mutations and ROR1-directed therapies can enhance the efficacy of treatment. In contrast, high ROR1 expression confers longer PFS to chemotherapy in the same group of patients. The role of chemotherapy and erlotinib in EGFR-mutant NSCLC patients with high ROR1 expression warrants further investigation.

| S-EPMC4367691 | biostudies-literature

Ornithine decarboxylase as a therapeutic target for endometrial cancer.

Project description:Ornithine Decarboxylase (ODC) a key enzyme in polyamine biosynthesis is often overexpressed in cancers and contributes to polyamine-induced cell proliferation. We noted ubiquitous expression of ODC1 in our published endometrial cancer gene array data and confirmed this in the cancer genome atlas (TCGA) with highest expression in non-endometrioid, high grade, and copy number high cancers, which have the worst clinical outcomes. ODC1 expression was associated with worse overall survival and increased recurrence in three endometrial cancer gene expression datasets. Importantly, we confirmed these findings using quantitative real-time polymerase chain reaction (qRT-PCR) in a validation cohort of 60 endometrial cancers and found that endometrial cancers with elevated ODC1 had significantly shorter recurrence-free intervals (KM log-rank p = 0.0312, Wald test p = 5.59e-05). Difluoromethylornithine (DFMO) a specific inhibitor of ODC significantly reduced cell proliferation, cell viability, and colony formation in cell line models derived from undifferentiated, endometrioid, serous, carcinosarcoma (mixed mesodermal tumor; MMT) and clear cell endometrial cancers. DFMO also significantly reduced human endometrial cancer ACI-98 tumor burden in mice compared to controls (p = 0.0023). ODC-regulated polyamines (putrescine [Put] and/or spermidine [Spd]) known activators of cell proliferation were strongly decreased in response to DFMO, in both tumor tissue ([Put] (p = 0.0006), [Spd] (p<0.0001)) and blood plasma ([Put] (p<0.0001), [Spd] (p = 0.0049)) of treated mice. Our study indicates that some endometrial cancers appear particularly sensitive to DFMO and that the polyamine pathway in endometrial cancers in general and specifically those most likely to suffer adverse clinical outcomes could be targeted for effective treatment, chemoprevention or chemoprevention of recurrence.

| S-EPMC5730160 | 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