MEX3A mediates p53 degradation to suppress ferroptosis and facilitate ovarian cancer tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA824850 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18687433_1.fastq.gz | Fastqsanger.gz | |||
| SRR18687433_2.fastq.gz | Fastqsanger.gz | |||
| SRR18687434_1.fastq.gz | Fastqsanger.gz | |||
| SRR18687434_2.fastq.gz | Fastqsanger.gz | |||
| SRR18687435_1.fastq.gz | Fastqsanger.gz |
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Project description:Epithelial ovarian cancer (OC) is a highly heterogeneous and malignant female cancer with an overall low survival rate. p53 mutation is a predominant genetic factor thought to be responsible for poor clinical outcome. Despite the fact that ovarian clear cell carcinoma (OCCC) shows more severe prognosis, drug resistance, metastasis and recurrence compared to other OC subtypes, mutations in p53 are much less frequent. The underlying mechanisms crucial for tumorigenesis and malignancy of OC harboring wild-type (WT) p53 remain poorly understood. We found that upregulation of MEX3A, which is a dual-function protein containing a RING finger domain and an RNA binding domain, was correlated with poor survival in OC. MEX3A overexpression enhanced tumorigenic activity in RMG-1 and OVISE OCCC cell lines. In contrast, depletion of MEX3A in PA-1 ovarian teratocarcinoma cells and TOV21G OCCC cells reduced cell survival and proliferative ability in cell-based assays, as well as inhibited tumor growth and prolonged survival in orthotopic xenograft models. MEX3A depletion did not alter p53 mRNA level but did increase the protein stability of WT p53. MEX3A-mediated p53 protein degradation was crucial to prevent ferroptosis and enhance tumorigenesis as p53 knockdown reversed the effects of MEX3A depletion. Together, our observations identified MEX3A as an important oncogenic factor promoting tumorigenesis in OC cells harboring WT p53.
2022-10-25 | GSE200509 | GEO
Project description:Epithelial ovarian cancer is a highly heterogeneous and malignant female cancer with an overall low survival rate. Mutations in p53 are prevalent in the major ovarian cancer histotype, high-grade serous ovarian carcinoma (HGSOC), while p53 mutations are much less frequent in other ovarian cancer subtypes, particularly in ovarian clear cell carcinoma (OCCC). Advanced stage OCCC with wild-type (WT) p53 has a worse prognosis and increased drug resistance, metastasis, and recurrence than HGSOC. The mechanisms responsible for driving the aggressiveness of WT p53-expressing ovarian cancer remain poorly understood. Here, we found that upregulation of MEX3A, a dual-function protein containing a RING finger domain and an RNA-binding domain, was critical for tumorigenesis in WT p53-expressing ovarian cancer. MEX3A overexpression enhanced the growth and clonogenicity of OCCC cell lines. In contrast, depletion of MEX3A in OCCC cells, as well as ovarian teratocarcinoma cells, reduced cell survival and proliferative ability. MEX3A depletion also inhibited tumor growth and prolonged survival in orthotopic xenograft models. MEX3A depletion did not alter p53 mRNA level but did increase p53 protein stability. MEX3A-mediated p53 protein degradation was crucial to suppress ferroptosis and enhance tumorigenesis. Consistently, p53 knockdown reversed the effects of MEX3A depletion. Together, our observations identified MEX3A as an important oncogenic factor promoting tumorigenesis in ovarian cancer cells expressing WT p53.SignificanceDegradation of p53 mediated by MEX3A drives ovarian cancer growth by circumventing p53 tumor suppressive functions, suggesting targeting MEX3A as a potential strategy for treating of ovarian cancer expressing WT p53.
| S-EPMC9845988 | biostudies-literature
Project description:Mex3a is an RNA binding protein of unknown function. To elucidate the contribution of Mex3a to tumoral heterogeneity, Mex3a KO organoids engineered by CRISPR were sequenced in three different conditions. Live organoids (DAPI negative) were sorted in Control, after 2 days of FOLFIRI and after 5 days of treatment. Two WT organoids (parental and a derived clone) and two KO (KO1 and KO2, two independent clones) were used for this experiment.
2022-05-16 | E-MTAB-11146 | biostudies-arrayexpress
Project description:Transcriptomic data related to 4 different subpopulations found in Mex3a Ki/+ Lgr5 Gfp in APCflfl adenomas in untreated animals. Adenomas where induced with 3%DSS and a single shot of 8mg/kg of Tamoxifen. The populations are refered as Mex3a + Lgr5, Mex3a- Lgr5+ Mex3a+ Lgr5- and Mex3a- Lgr5- according to the flow cytometry profile. Cells were isolated using FACsARIA (BD)
2022-05-12 | GSE163171 | GEO
Project description:The effort to better understand intestinal stem cell (ISC) identity and regulation remains a challenge. We have been studying the RNA-binding protein MEX3A as a putative ISC marker. In that context, we have generated the first Mex3a knockout (KO) mouse model and show MEX3A is crucial for maintenance of the Lgr5+ ISC pool. As part of a phenotypic characterization pipeline, we have performed transcriptomic profiling (RNA-sequencing) of isolated Mex3a KO small intestinal crypts and compared it against small intestinal crypts isolated from age-matched wild-type controls.
2020-02-13 | GSE141191 | GEO
Project description:Neural stem cells (NSCs) in the adult mammalian subependymal zone maintain a glial identity and the developmental potential to generate neurons during the lifetime. Production of neurons from these NSCs is not direct but follows an orderly pattern of cell progression which allows the gradual increase in pro-neural factors needed for neuronal fate. Although little is known about how stemness is molecularly balanced with the acquisition of the cell competence for neuronal differentiation along the lineage, regulated translation of existing transcripts is a potential mechanism to avoid the critical challenge posed by genes that encode proteins with conflicting functions, i.e. self-renew or differentiate. Here, we identify MEX3A as a post-transcriptional regulator of a set of stemness-associated transcripts at critical transitions in the subependymal neurogenic lineage. MEX3A regulates a quiescence-related RNA signature in activated NSCs that is needed for the return to quiescence, playing a role in the long-term maintenance of the NSC pool. Furthermore, it is required for the repression of the same program at the onset of neuronal differentiation. Our data indicate that MEX3A acts via a number of downstream targets to function as a pivotal regulator of adult mammalian neurogenesis.
2022-12-19 | GSE184404 | GEO
Project description:Mex3a labells a subpopulation of Cancer Stem cells defined by their slow proliferative behaviour. Nevertheless, the precise function of MEX3A is unknown, although it plays a role in chemoresistance. The Mex3a KO adenomas are less chemoresistant compared to their WT controls. We used microarrays to elucidate changes in gene expression in cells with the Mex3a promoter active (tomato expressing cells)
2022-05-12 | GSE187650 | GEO
Project description:Circular RNAs (circRNAs) have been implicated in the tumorigenesis of non-small cell lung cancer (NSCLC). Ferroptosis is considered a mechanism to suppress tumorigenesis. Herein, we identified a novel downregulated circRNA, circPOLA2 (hsa_circ_0004291), in NSCLC tissues and found that it was correlated with advanced clinical stage in patients. Nuclear-cytoplasmic fractionation assays and FISH assays confirmed that circPOLA2 was predominantly localized in the cytoplasm. Overexpression of circPOLA2 promoted lipid peroxidation and ferroptosis in NSCLC cells, thereby inhibiting cell proliferation and migration, while knockdown of circPOLA2 exerted the opposite effects. Mechanistically, circPOLA2 interacted with Merlin, a critical regulator of the Hippo pathway, and restricted Merlin phosphorylation at S518, leading to the activation of the Hippo pathway. In addition, circPOLA2 enhanced ferroptosis in NSCLC cells by activating the Hippo pathway. Together, circPOLA2 sensitizes cells to ferroptosis and suppresses tumorigenesis in NSCLC by facilitating Merlin-mediated activation of the Hippo signaling pathway.
2024-08-20 | GSE254362 | GEO
Project description:The intestinal epithelium is continuously regenerated by highly proliferative Lgr5+ intestinal stem cells (ISCs). The existence of a population of quiescent ISCs has been suggested yet its identity and features remain controversial. Here we describe that the expression of the RNA-binding protein Mex3a labels a subpopulation of Lgr5+ cells that divide less frequently and contribute to regenerate all intestinal lineages with slow kinetics. Single cell transcriptomic analysis revealed two classes of Lgr5-high cells, one of them defined by the Mex3a-expression program and by low levels of proliferation genes. Lineage tracing experiments show that large fraction of Mex3a+ cell population is continuously recalled into the rapidly dividing self-renewing ISC pool in homeostatic conditions. Chemotherapy and radiation target preferentially rapidly dividing Lgr5+ cells but spare the Mex3a-high/Lgr5+ population, which helps sustain the renewal of the intestinal epithelium during treatment.
2017-03-14 | GSE90856 | GEO