PI3K/mTOR dual inhibitor GSK458 and arsenic trioxide exert synergistic anti-tumor effects against ovarian clear cell carcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE270218 | GEO | 2024/06/18
REPOSITORIES: GEO
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Project description:To identify genes critical for the proliferation of ovarian clear cell carcinoma (OCCC), we performed CRISPR/CAS9 screens against the OCCC cell lines OVICE, ES2, TOV21G and JHOC5 using the TKOv3 sgRNA library.
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Project description:Ovarian cancer has one of the worst prognoses among gynecologic malignancies. About 60% of ovarian cancer cases are diagnosed at Stages III and IV, and their five-year survival rate is less than 30%. Ovarian cancer is classified into four major histological subtypes; serous, clear cell, endometrioid and mucinous. Ovarian clear cell carcinoma (OCCC) is less sensitive to conventional platinum-based chemotherapy and has worse prognosis than other subtypes. In this study, we attempted to identify novel molecular targets critical for the proliferation and tumorigenicity of OCCC using the CRISPR/Cas9 system, and identified some genes as important candidates. Some of these candedates were upregulated in ovarian cancer tissue, especially OCCC. Our results suggest that not only may be these candedates a promising diagnostic maker for OCCC, drugs against these candedates would be useful for the therapeutic treatment of OCCC.
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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:Ovarian clear cell carcinoma (OCCC) shows unique clinical features including an association with endometriosis and poor prognosis. We previously reported that the contents of endometriotic cysts, especially high concentrations of free iron, are a possible cause of OCCC carcinogenesis through iron-induced persistent oxidative stress. In this study, we conducted gene expression microarray analysis using 38 ovarian cancer cell lines and identified genes commonly expressed in both OCCC cell lines and clinical samples, which comprise an OCCC gene signature. The OCCC signature reproducibly predicts OCCC specimens in other microarray data sets, suggesting that this gene profile reflects the inherent biological characteristics of OCCC. The OCCC signature contains known markers of OCCC, such as hepatocyte nuclear factor-1b (HNF-1b) and versican (VCAN), and other genes that reflect oxidative stress. Expression of OCCC signature genes was induced by treatment of immortalized ovarian surface epithelial cells with the contents of endometriotic cysts, indicating that the OCCC signature is largely dependent on the tumor microenvironment. Induction of OCCC signature genes is at least in part epigenetically regulated, as we found hypomethylation of HNF-1b and VCAN in OCCC cell lines. This genomewide study indicates that the tumor microenvironment induces specific gene expression profiles that contribute to the development of distinct cancer subtypes. Affymetrix Human Genome U133A 2.0 Array was conducted for 38 ovarian cancer cell lines (13 OCCC cell lines and 25 non-OCCC cell lines). All specimens were arrayed in parallel and used for RMA normalization.
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Project description:Ovarian clear cell carcinoma (OCCC) shows unique clinical features including an association with endometriosis and poor prognosis. We previously reported that the contents of endometriotic cysts, especially high concentrations of free iron, are a possible cause of OCCC carcinogenesis through iron-induced persistent oxidative stress. In this study, we conducted gene expression microarray analysis using 38 ovarian cancer cell lines and identified genes commonly expressed in both OCCC cell lines and clinical samples, which comprise an OCCC gene signature. The OCCC signature reproducibly predicts OCCC specimens in other microarray data sets, suggesting that this gene profile reflects the inherent biological characteristics of OCCC. The OCCC signature contains known markers of OCCC, such as hepatocyte nuclear factor-1b (HNF-1b) and versican (VCAN), and other genes that reflect oxidative stress. Expression of OCCC signature genes was induced by treatment of immortalized ovarian surface epithelial cells with the contents of endometriotic cysts, indicating that the OCCC signature is largely dependent on the tumor microenvironment. Induction of OCCC signature genes is at least in part epigenetically regulated, as we found hypomethylation of HNF-1b and VCAN in OCCC cell lines. This genomewide study indicates that the tumor microenvironment induces specific gene expression profiles that contribute to the development of distinct cancer subtypes.
2011-05-16 | GSE29175 | GEO
Project description:Ovarian clear cell carcinoma (OCCC) is a morphologically and biologically distinct subtype of ovarian carcinomas. We previously reported a gene expression profile characteristic of OCCC (OCCC signature), which contains hepatocyte nuclear facter-1b ( HNF-1b). To elucidate the biological role of HNF-1b in OCCC, we performed the suppression of the HNF-1b expression in human ovarian cancer cell line RMG2 using short hairpin RNA. We are now evaluating the functional effect using these cells. Affimetrix Human Genome U133A plus 2.0 chips was conducted for HNF1b knockdown and non-silencing cells (five replicates each for RMG2-HNF1b-sh1 and RMG2-HNF1b-sh2, ten replicates for the RMG2-control). All specimens were arrayed in parallel and used for RMA normalization.
2012-04-30 | E-GEOD-37290 | biostudies-arrayexpress
Project description:Ovarian clear cell carcinoma (OCCC) is a cancer of unmet need characterized by ARID1A mutation. Prior work identified an ARID1A/ATR synthetic lethality, information that led to phase II clinical trials. Using genome-wide CRISPR-Cas9 mutagenesis and interference screens, we identified protein phosphatase 2A (PP2A) subunits, including PPP2R1A, as determinants of ATRi sensitivity in ARID1A mutant OCCC. Analysis of an OCCCs cohort indicated that >1/3 possessed both PPP2R1A and ARID1A loss-of-function mutations. CRISPR-prime editing demonstrated that oncogenic PPP2R1A p.R183 missense mutations enhance in vitro and in vivo ATRi sensitivity in ARID1A mutant OCCC. OCCC patients with both ARID1A and PPP2R1A mutations also showed clinical responses to ATRi in a phase II trial. Mechanistically, this synthetic lethal effect is dependent upon WNK1 kinase, which opposes PP2A function. This data suggests that co-occurrence of PPP2R1A and ARID1A mutations in OCCC should be assessed as a biomarker of ATRi response in on-going clinical trials.
2023-05-10 | PXD040422 | Pride
Project description:While thousands of previously unannotated small and alternative open reading frames (alt-ORFs) have recently been revealed in the human genome, the functions of only a handful are currently known, leaving open the question of their biological significance as a class. Using a proteomic strategy for discovery of unannotated short open reading frames in human cells, we report the detection of alt-RPL36, a 148-amino acid protein co-encoded with and overlapping human RPL36. Alt-RPL36 interacts with TMEM24, which transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 in HEK 293T cells increased PI(4,5)P2 levels in the plasma membrane and upregulated the PI3K-AKT-mTOR signaling pathway. Remarkably, we find that four serine residues of alt-RPL36 are phosphorylated, and mutation of these four serines to alanine abolished the interaction with TMEM24 and regulation of PI3K signaling. These results implicate alt-RPL36 as a novel regulator of PI(4,5)P2 synthesis upstream of the PI3K-AKT-mTOR signaling pathway, and the first example of a phosphorylated alt-ORF product. More broadly, both alt-RPL36 and RPL36 regulate protein synthesis and cell growth via different molecular mechanisms – AKT signaling and ribosome composition, respectively. One human transcript can therefore express two sequence-independent polypeptides from overlapping ORFs that regulate the same processes via distinct mechanisms.
2020-12-07 | PXD018268 | Pride