Targeted suppression of ZNF217-induced AKT signaling inhibits tumor growth and metastasis in osteosarcoma
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ABSTRACT:
PROVIDER: PRJNA614505 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11394426_1.fastq.gz | Fastqsanger.gz | |||
| SRR11394426_2.fastq.gz | Fastqsanger.gz | |||
| SRR11394427_1.fastq.gz | Fastqsanger.gz | |||
| SRR11394427_2.fastq.gz | Fastqsanger.gz | |||
| SRR11394428_1.fastq.gz | Fastqsanger.gz |
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Project description:We previously identified ZNF217 as an oncogenic driver of a subset of osteosarcomas (OSAs) using the Sleeping Beauty (SB) transposon system. Here, we followed up investigating the role of ZNF217 in OSA and combined these studies with an orthotopic preclinical animal model and culture experiments. We found that targeting ZNF217-induced AKT signaling with a small molecule inhibitor is a promising approach to treating ZNF217+ OSAs. Here, we demonstrate that ZNF217 is involved in numerous facets of OSA transformation including proliferation, cell motility, colony formation, and ultimately promoting OSA growth, progression, and metastasis in part through AKT survival pathway modulation. Preclinical blockade of AKT signaling with nucleoside analogue triciribine (TCN) in ZNF217+ orthotopically-injected OSA cell lines reduced tumor growth, metastasis, and was well-tolerated. TCN treatment was also found to synergize with common broad-spectrum chemotherapeutic doxorubicin. Our data demonstrate that TCN treatment may be a relevant and efficacious therapeutic strategy for OSA patients with ZNF217+ and p-AKTSer473-rich tumors. With the recent revitalization of triciribine for clinical studies in other solid cancers (PTX-200, Prescient Therapeutics), our study provides rationale for further evaluation preclinically with the purpose of clinical evaluation in patients with incurable, ZNF217+ OSA.
2020-03-24 | GSE147413 | GEO
Project description:Chemoresistance is one of the major causes of poor prognosis in osteosarcoma. Thus far, the therapeutic alternative for osteosarcoma is quite limited, thereby increasing sensitivity of the currently used drugs is an effective way to improve outcome of patients. In this study, through a Kinome-wide CRISPR screen, we identified PRKDC as a critical determinant of Doxorubicin (DOX) sensitivity in osteosarcoma. Clinical sample analysis and functional experiments demonstrated that PRKDC is hyperactivated in osteosarcoma and that knockdown of PRKDC significantly increased sensitivity of osteosarcoma to DOX. Mechanistically, PRKDC could recruit and bind with GDE2 to augment the stability of GNAS. The increased GNAS protein subsequently activate Akt S473 and T308 phosphorylation and mediated DOX sensitivity. We also showed that the PRKDC inhibitor AZD7648 and DOX could synergize with each other and intensely suppressed the growth of osteosarcoma in mice xenograft models and human organoids. In conclusion, these results revealed a novel PRKDC-GDE2-GNAS-Akt regulatory axis in DOX sensitivity and provided targetable candidates for improving therapeutic efficacy of DOX in osteosarcoma.
2024-06-14 | GSE268415 | GEO
Project description:Osteosarcoma is the third most common cancer in adolescence and the first common primary malignant tumor of bone. The long-term prognosis of osteosarcoma, especially for unresectable and metastatic tumors, still remains unsatisfactory in the past decades. In this study, we systematically investigated the antitumor effect of imperatorin (IMP), a small molecule extracted from Angelica dahurica, in human osteosarcoma cells. The results showed that IMP triggered time-dependent and dose-dependent inhibition of tumor growth mainly by inducing autophagy promotion and G0/G1 phase arrest in vitro and in vivo. Besides, IMP treatment elevated the expression level of PTEN and p21, down-regulated the phosphorylation of AKT and mTOR. In contrast, the inhibition of PTEN using Bpv (HOpic), a potential and selective inhibitor of PTEN, concurrently rescued IMP-induced autophagy promotion, cell cycle arrest and inactivation of PTEN-PI3K-AKT-mTOR/p21 pathway. Taken together, our data revealed that imperatorin induced autophagy and cell cycle arrest through PTEN-PI3K-AKT-mTOR/p21 signaling pathway by targeting and up-regulating PTEN in human osteosarcoma cells. Hence, imperatorin is a desirable candidate for clinical treatments of osteosarcoma.
2021-12-23 | GSE180321 | GEO
Project description:The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20-30% of primary human breast cancers and that correlates with poor prognosis. We show Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We demonstrate that the nucleoside analog triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance, and inhibits signaling events (e.g., P-AKT, P-MAPK) in vivo. Our data suggest ZNF217 is a biomarker of poor prognosis and a therapeutic target in breast cancer patients, and triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Since ZNF217 is amplified in numerous cancers, these results have implications for other cancers. Total RNA was isolated from samples overexpressing ZNF217 (3 Primary and 5 SCp2). RNA was also harvested from each cell line expressing a vector control to use as a reference for each microarray sample analyzed. Total RNA was hybridized to mouse MEEBO arrays as described (http://www.microarray.org/sfgf/meebo.do). Samples were verified to have strong overexpression of ZNF217 by qRT-PCR or Western analysis.
2012-05-17 | E-GEOD-24727 | biostudies-arrayexpress
Project description:The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20-30% of primary human breast cancers and that correlates with poor prognosis. We show Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We demonstrate that the nucleoside analog triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance, and inhibits signaling events (e.g., P-AKT, P-MAPK) in vivo. Our data suggest ZNF217 is a biomarker of poor prognosis and a therapeutic target in breast cancer patients, and triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Since ZNF217 is amplified in numerous cancers, these results have implications for other cancers.
2012-05-18 | GSE24727 | GEO
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Project description:EPDR1 inhibits proliferation and matastasis of ovarian cancer through PI3K/AKT pathway
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Project description:SaOS2 osteosarcoma cells were cultured with or without atorvastatin (10 µM) for 6, 15 or 24h (2 biological replcates). RNA were isolated and hybridized to RNG microarrays. Background Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and poor survival rate for patients. Methods We previously showed that the HMGCoA reductase inhibitors statins exhibit anti-tumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify cyr61/CCN1 as a new target of statins. Modulations of expression of cyr61 were performed in human and murine osteosarcoma cell lines to investigate in vitro cell viability, migratory potential and invasiveness. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients using tissue microarray. Tumor behavior and metastases occurence were analysed by IM injection of modified osteosarcoma cells to BALB/c mice. Results Transcriptome comparisons revealed that statins down-regulate cyr61 expression in SaOS2 cells. Cyr61 silencing in human and murine osteosarcoma cell lines enhanced cell death, but reduced cell migration and cell invasion compared to parental cells whereas cyr61 overexpression had opposite effects. Tissue microarray analysis demonstrated that cyr61 protein expression is higher in human osteosarcoma compared to normal bone tissue and is further increased in metastatic tissues. In vivo, cyr61 overexpression in osteosarcoma cells enhanced lung metastases development whereas cyr61 silencing strongly reduced metastases in mice. Conclusion The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma. Dye balance-experiment comparing atorvastatin versus untreated cells at 6, 15 and 24 hours using 2 biological replicates.
2011-02-22 | E-GEOD-24401 | biostudies-arrayexpress