Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

XPO1 R749Q Mutation Drives Endometrial Cancer Progression by Activating HIF-1/2α–AXL–PI3K/MAPK Signaling

ABSTRACT: The tumor driver gene XPO1 (exportin-1) exhibits high-frequency mutations in endometrial cancer (approximately 6%), with two hotspot mutation sites identified as E571K and R749Q. However, the molecular mechanisms by which XPO1 mutations influence the initiation and progression of endometrial cancer remain unclear. Here, we we discovered an unexpected role of XPO1 R749Q in regulating AXL expression in EC.This study reveals that the XPO1 R749Q mutation drives malignant transformation in endometrial cancer, including enhanced proliferation, migration, and invasion, by activating the PI3K-Akt and MAPK signaling pathways through the HIF1α/HIF2α-AXL axis. Importantly, the oncogenic effects mediated by the XPO1 R749Q mutation can be effectively suppressed by the AXL inhibitor cabozantinib and the XPO1 inhibitor KPT-330. These findings elucidate the molecular mechanism by which the XPO1 R749Q mutation contributes to endometrial carcinogenesis and provide a compelling therapeutic rationale for targeting the XPO1 R749Q-mutant subtype of endometrial cancer with cabozantinib and KPT-330

ORGANISM(S): Homo sapiens

PROVIDER: GSE292576 | GEO | 2026/06/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

XPO1 blockade with KPT-330 promotes apoptosis in Cutaneous T- cell Lymphoma by activating the p53-p21 and p27 pathways

Project description:To assess the effects of XPO1 inhibition with small molecule inhibitor KPT-330 on Cutaneous T-cell Lymphoma after 48 hours of treatment

2024-04-23 | GSE262491 | GEO

Analysis of gene expression changes in KPT330-treated HMLE cells transduced to stably overexpress SNAI1

Project description:HMLE-SNAIL cell cultures were treated with KPT330 drug (KPT, 150 nanomolar) or vehicle (DMSO) for 24 hours, in parallel quadruplicates. KPT-330 is an Exportin 1 (XPO1) inhibitor with possible pluripotent or unexpected effects on cell signaling. Total RNA was isolated and analyzed in an Agilent two-color experiment, where four biological replicates of each condition were directly compared, expression ratios are KPT-treated condition relative to control (DMSO vehicle-treated) The experiment object was to identify genes that displayed significantly altered expression in response to KPT treatment inorder to confirm on-target drug impact and elucidate other potential effects in this cell line model.

2015-08-31 | E-GEOD-69326 | biostudies-arrayexpress

XPO1 amplification abrogates the effects of E571K XPO1 mutation in B-cell lymphoma

Project description:XPO1 gene encodes exportin 1 (XPO1) that controls the nuclear export of cargo proteins and RNAs. Almost 25% of primary mediastinal B-cell lymphomas (PMBL) and classical Hodgkin lymphomas (cHL) cases harboured a recurrent XPO1 point mutation (NM_003400, chr2:g61718472C>T) resulting in the E571K modification within the hydrophobic groove of the protein, the site of cargo proteins binding. We investigated the functional impact of XPO1E571K mutation using cell lines having various XPO1 status. We first confirmed that the mutation was present both within the XPO1 mRNA and the corresponding protein. In the U2940 cell line having a wild-type (wt) XPO1 gene, we introduced the E571K mutation using several CRISPR-Cas9 strategies. Using a barcoding method to trace the mutation, we observed that the mutation gave no advantage in vitro. Indeed, the effects of XPO1E571K mutation were hidden by the presence of the XPO1 wt allele. Strikingly, XPO1E571K mutation never occurred as homozygous or hemizygous in our patients�� cohort. We further showed that XPO1E571K mutation modified selinexor binding to XPO1 and in turn, its sensitivity to this drug. We concluded that the balance between the wild-type and the mutated allele of XPO1 is a key element in defining XPO1 functions and oncogenic properties.

2020-10-01 | PXD016916 | Pride

CRISPR-Cas9 screening of KSHV-transformed cells identifies XPO1 as a vulnerable target of cancer cells by inducing p62 SQSTM1-mediated p53 activation in PML bodies

Project description:Mislocalization of oncogenes and tumor suppressors resulting from aberrant nuclear export promotes uncontrolled cell proliferation and growth transformation of cancer cells. We performed a genome-wide CRISPR-Cas9 screening in matched primary and KSHV-transformed cells, and identified genes that were pro-growth and growth-suppressive of both types of cells, of which exportin XPO1 was a critical factor for the survival of transformed cells. Using XPO1 inhibitor KPT-8602 and by siRNA-mediated knockdown, we confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells, as well as cell lines of other types of cancer including gastric cancer and liver cancer. XPO1 inhibition induced cell cycle arrest and p53 activation, which depended on the formation of PML nuclear bodies. Furthermore, XPO1 induced relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. Our findings highlight a novel mechanism of p53 activation and identify XPO1 as a vulnerable target of cancer cells.

2019-05-21 | GSE125507 | GEO

Targeting XPO1/DDX1-mediated nuclear export of R-loops in inflammaging [cytoDRIP-seq]

Project description:R-loops are three-stranded nucleic acids containing DNA-RNA hybrid and a third displaced ssDNA and are widely distributed across the genome. Dysregulation in R-loop dynamics cause DNA damage and genome instability. Although its role has been extensively investigated in various pathological processes, whether R-loops are perturbed during senescence and tissue aging remains unclear. Here we observe a global decline in R-loop stalling across the genome during senescence. While R-loops in nucleus were dramatically decreased, we detected their significant accumulation in the cytoplasm in senescent cells. We identify their source as nuclear R-loops with a specific enrichment in alpha-satellites, a subset of repetitive elements. Notably, these cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCF) to induce cGAS-STING innate immune response, and this nucleocytoplasmic transport is dependent on exportin 1 (XPO1)/DEAD-Box helicase 1 (DDX1) complex. Targeting R-loop nuclear export by XPO1 inhibitor Selinexor (KPT-330) suppresses the inflammatory response in senescent cells and relieves inflammaging in aged mice. In summary, our findings linked aberrant accumulation of cytoplasmic R-loops to inflammaging, rendering their nucleocytoplasmic transport process an ideal target for suppressing inflammaging.

2026-04-30 | GSE296055 | GEO

Targeting XPO1/DDX1-mediated nuclear export of R-loops in inflammaging [RIP-Seq]

2026-04-30 | GSE296054 | GEO

Targeting XPO1/DDX1-mediated nuclear export of R-loops in inflammaging [CUT&Run]

2026-04-30 | GSE296056 | GEO

Identification of Nuclear Export Inhibitor-Based Combination Therapies in Preclinical Models of Triple-Negative Breast Cancer

Project description:An estimated 284,000 Americans will be diagnosed with breast cancer in 2021. Of these individuals, 15-20% will be diagnosed with basal-like triple-negative breast cancer (TNBC), which is known to be highly metastatic. Chemotherapy is standard of care for TNBC patients, but acquired chemoresistance is a common clinical problem. There is currently a lack of alternative, targeted treatment strategies for TNBC; this study sought to identify novel therapeutic combinations to treat basal-like TNBCs. For these studies, a set of four human basal-like TNBC cell lines was utilized to determine the cytotoxicity profile of 1,363 unique clinically-used drugs. Ten promising therapeutic candidates were identified, and synergism studies were performed in vitro. Two drug combinations that included KPT-330, an XPO1 inhibitor, were synergistic in all four cell lines. In vivo testing of four basal-like patient-derived xenografts identified a combination, KPT-330 and GSK2126458 (a PI3K/mTOR inhibitor), that decreased tumor burden in mice significantly more than monotherapy with either single agent. Bulk and single-cell RNA-sequencing, immunohistochemical studies, and analysis of published genomic datasets found that XPO1 was abundantly expressed in human basal-like TNBC cell lines, patient-derived xenografts, and patient tumor samples; within basal-like patients, XPO1 overexpression was associated with greater rates of metastases. These studies identify a promising new combination therapy for patients with basal-like TNBC.

2021-10-20 | GSE174391 | GEO

XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

Project description:The five-year survival rate remains less than 50% for high-risk neuroblastoma patients, few of them show effective response to current chemotherapy drugs. It is urgent to identify new therapeutic targets and corresponding drugs for high-risk neuroblastoma. Exportin-1(XPO1), also known as chromosomal region maintenance 1 (CRM1), plays important roles in the progress of tumorigenesis. However, the prognostic and therapeutic values of XPO1 in neuroblastoma have not been reported. Here, our results showed that overexpression of XPO1 was significantly associated with poor clinical characteristics and prognosis of neuroblastoma patients. The specific inhibitor of XPO1 suppressed neuroblastoma cell growth both in vitro and in vivo. Specifically, inhibition of XPO1 suppressed neuroblastoma cells proliferation and induced cell apoptosis by FOXO1 and RB1 nuclear accumulation in neuroblastoma through inhibiting PI3K/AKT pathway, and induced G0/G1 phase cell arrest by activating P53 function. Together, XPO1 is a promising prognostic indicator for neuroblastoma and a novel target for antitumor treatment by selective inhibitor verdinexor (KPT-335).

2021-08-18 | GSE163987 | GEO

High-throughput mRNA sequencing of CLL cells containing an E571K XPO1 mutations

Project description:Purpose: Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood. Thus, we aimed to identify disrupted cellular pathways in response to the E571K XPO1 mutation, the mutation most frequently cited in CLL patients, via high-throughput RNA-sequencing Results & Conclusion: Multidimensional scaling (MDS) analysis of the top 1000 most variable genes demonstrated distinctly unique clustering along the first dimension for XPO1-E571K patient and XPO1-wt patient samples. This clustering pattern was driven by a number of genes that were either over- or under-expressed in XPO1-E571K patient cells, contributing to a unique gene expression pattern in patients with this mutation signature.

2021-01-21 | GSE163370 | GEO

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