C-Myc targeted genes validated by PCR array in STEAP1-silenced HepG2 cells.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE173813 | GEO | 2021/05/05
REPOSITORIES: GEO
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Project description:c-Myc targeted genes validated by PCR array in STEAP1-silenced HepG2 cells.
| PRJNA727168 | ENA
Project description:Goal: identification of differentially expressed genes after STEAP1 silencing. Ewing tumors (ET) are characterized by oncogenic EWS/ETS translocations and early metastasis. STEAP1 is a membrane-bound channel protein of unkown function. While overexpressed in many cancers, STEAP1 expression is strongly restricted to mesenchymal stem cells, prostate and urothelium among benign tissues. Here we show that STEAP1 is a direct transcriptional target of EWS/FLI1 and critical for ET malignancy. We demonstrate that STEAP1 is most prominently expressed in ET among sarcomas and provide further evidence for the concept of STEAP1 as a universal diagnostic marker for carcinomas. Using RNA interference we determined that STEAP1 promotes cellular invasiveness and anchorage-independent growth in vitro and accelerates tumor growth and metastasis in vivo. Transcriptome and proteome analyses as well as functional studies reveal that STEAP1 contributes to the generation of reactive oxygen species that in turn regulate the levels of redox-sensitive signaling molecules and pro-metatstatic genes. In synopsis, these data illuminate the hitherto unkown oncogenic function of STEAP1 as a redox-modulator in ET and point to a potential role of STEAP1 as universal drug target for anti-cancer therapy. 6 samples (3x A673 cells; 3x SK-N-MC cells); for each cell line one sample was transfected with control non silencing siRNA and two samples with different STEAP1 siRNAs (siSTEAP1_2 and siSTEAP1_3).
2012-01-01 | E-GEOD-26422 | biostudies-arrayexpress
Project description:Goal: identification of differentially expressed genes after STEAP1 silencing. Ewing tumors (ET) are characterized by oncogenic EWS/ETS translocations and early metastasis. STEAP1 is a membrane-bound channel protein of unkown function. While overexpressed in many cancers, STEAP1 expression is strongly restricted to mesenchymal stem cells, prostate and urothelium among benign tissues. Here we show that STEAP1 is a direct transcriptional target of EWS/FLI1 and critical for ET malignancy. We demonstrate that STEAP1 is most prominently expressed in ET among sarcomas and provide further evidence for the concept of STEAP1 as a universal diagnostic marker for carcinomas. Using RNA interference we determined that STEAP1 promotes cellular invasiveness and anchorage-independent growth in vitro and accelerates tumor growth and metastasis in vivo. Transcriptome and proteome analyses as well as functional studies reveal that STEAP1 contributes to the generation of reactive oxygen species that in turn regulate the levels of redox-sensitive signaling molecules and pro-metatstatic genes. In synopsis, these data illuminate the hitherto unkown oncogenic function of STEAP1 as a redox-modulator in ET and point to a potential role of STEAP1 as universal drug target for anti-cancer therapy.
2012-01-01 | GSE26422 | GEO
Project description:Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. Here, we identified broad expression of STEAP1 relative to the established theranostic target prostate-specific membrane antigen (PSMA) in a series of lethal metastatic prostate cancers which prompted the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrated reactivity in low antigen density, antitumor activity across multiple metastatic human and mouse prostate cancer models, and preliminary safety in a human STEAP1 knock-in mouse model. In human-in-mouse and mouse-in-mouse studies, STEAP1 CAR T cell therapy yielded effective tumor responses, but antigen escape was appreciated as a recurrent mechanism of treatment resistance and STEAP1 antigen loss was associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein as an adjunct to STEAP1 CAR T cell therapy enhanced antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading. In summary, we describe the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, characterize a STEAP1 CAR T cell therapy with preclinical evidence of potency and safety, and nominate a combinatorial immunotherapy strategy to overcome barriers to the efficacy of CAR T cell therapy in advanced prostate cancer.
2023-04-03 | GSE228884 | GEO
Project description:Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. Here, we identified broad expression of STEAP1 relative to the established theranostic target prostate-specific membrane antigen (PSMA) in a series of lethal metastatic prostate cancers which prompted the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrated reactivity in low antigen density, antitumor activity across multiple metastatic human and mouse prostate cancer models, and preliminary safety in a human STEAP1 knock-in mouse model. In human-in-mouse and mouse-in-mouse studies, STEAP1 CAR T cell therapy yielded effective tumor responses, but antigen escape was appreciated as a recurrent mechanism of treatment resistance and STEAP1 antigen loss was associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein as an adjunct to STEAP1 CAR T cell therapy enhanced antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading. In summary, we describe the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, characterize a STEAP1 CAR T cell therapy with preclinical evidence of potency and safety, and nominate a combinatorial immunotherapy strategy to overcome barriers to the efficacy of CAR T cell therapy in advanced prostate cancer.
2023-03-22 | GSE214584 | GEO
Project description:Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. Here, we identified broad expression of STEAP1 relative to the established theranostic target prostate-specific membrane antigen (PSMA) in a series of lethal metastatic prostate cancers which prompted the development of a STEAP1-directed chimeric antigen receptor (CAR) T cell therapy. STEAP1 CAR T cells demonstrated reactivity in low antigen density, antitumor activity across multiple metastatic human and mouse prostate cancer models, and preliminary safety in a human STEAP1 knock-in mouse model. In human-in-mouse and mouse-in-mouse studies, STEAP1 CAR T cell therapy yielded effective tumor responses, but antigen escape was appreciated as a recurrent mechanism of treatment resistance and STEAP1 antigen loss was associated with diminished tumor antigen processing and presentation. The application of tumor-localized interleukin-12 (IL-12) therapy in the form of a collagen binding domain (CBD)-IL-12 fusion protein as an adjunct to STEAP1 CAR T cell therapy enhanced antitumor efficacy by remodeling the immunologically cold tumor microenvironment of prostate cancer and combating STEAP1 antigen escape through the engagement of host immunity and epitope spreading. In summary, we describe the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, characterize a STEAP1 CAR T cell therapy with preclinical evidence of potency and safety, and nominate a combinatorial immunotherapy strategy to overcome barriers to the efficacy of CAR T cell therapy in advanced prostate cancer.
2023-03-22 | GSE214583 | GEO
Project description:Prostate cancer (PCa) continues to be one of the most common cancers in men worldwide. The six transmembrane epithelial antigen of the prostate 1 (STEAP1) protein is overexpressed in several types of human tumours, particularly in PCa. Our research group has demonstrated that STEAP1 overexpression is associated with PCa progression and aggressiveness. Therefore, understanding the cellular and molecular mechanisms triggered by STEAP1 overexpression will provide important insights to delineate new strategies for PCa treatment. In the present work, a proteomic strategy was used to characterize the intracellular signalling pathways and the molecular targets downstream of STEAP1 in PCa cells. A label-free approach was applied using an Orbitrap LC-MS/MS system to characterize the proteome of STEAP1-knockdown PCa cells. More than 6700 proteins were identified, of which a total of 526 proteins were found differentially expressed in scramble siRNA versus STEAP1 siRNA (234 proteins up-regulated and 292 proteins down-regulated). Bioinformatics analysis allowed us to explore the mechanism through which STEAP1 exerts influence on PCa, revelling that endocytosis, RNA transport, apoptosis, aminoacyl-tRNA biosynthesis and metabolic pathways are the biological processes where STEAP1 is involved. By immunoblotting, it was confirmed that STEAP1 knockdown induced the up-regulation of cathepsin B, intersectin-1 and syntaxin 4,while it down-regulation HRas, PIK3C2A and DIS3. These finding suggested that blocking STEAP1 might be a strategy to activate apoptosis and endocytosis, and diminish cellular metabolism and intercellular communication, leading to inhibition of PCa progression.
2023-10-18 | PXD037834 | Pride
Project description:RNA-seq was performed to confirm the effect of dMyc overexpression or RNAi repression on conserved Myc targets in the Drosophila wing disc.
2022-04-26 | E-MTAB-9328 | biostudies-arrayexpress
Project description:To identify proteomic signatures associated with hepatocellular carcinoma driven by MYC overexpression, proteomics was performed on the LAP-tTA/tetO-MYC mouse conditional liver cancer model. Upon MYC activation, mice form liver cancer. Differential proteomics was performed in "MYC on" (MYC-HCC) mouse liver tumors versus mouse control normal liver tissue (where MYC was not overexpressed to drive tumorigenesis -- "MYC off").
2022-10-12 | PXD031478 | Pride
Project description:High expression of MYC and its target genes define a subset of germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL) associated with poor outcomes. Half of these high-grade cases show chromosomal rearrangements between the MYC locus and heterologous enhancer-bearing loci, while focal deletions of the adjacent non-coding gene PVT1 are enriched in MYC-intact cases. To identify genomic drivers of MYC activation, we used high-throughput CRISPR-interference (CRISPRi) profiling of candidate enhancers in the MYC locus and rearrangement partner loci in GCB-DLBCL cell lines and mantle cell lymphoma (MCL) comparators that lacked common rearrangements between MYC and immunoglobulin (Ig) loci. Rearrangements between MYC and non-Ig loci were associated with unique dependencies on specific enhancer subunits within those partner loci. Notably, fitness dependency on enhancer modules within the BCL6 super-enhancer (BCL6-SE) cluster regulated by a transcription factor complex of MEF2B, POU2F2, and POU2AF1 was higher in cell lines bearing a recurrent MYC::BCL6-SE rearrangement. In contrast, GCB-DLBCL cell lines without MYC rearrangement were highly dependent on a previously uncharacterized 3’ enhancer within the MYC locus itself (GCBME-1), that is regulated in part by the same triad of factors. GCBME-1 is evolutionarily conserved and active in normal germinal center B cells in humans and mice, suggesting a key role in normal germinal center B cell biology. Finally, we show that the PVT1 promoter limits MYC activation by either native or heterologous enhancers and demonstrate that this limitation is bypassed by 3’ rearrangements that remove PVT1 from its position in cis with the rearranged MYC gene.
2025-03-06 | GSE242077 | GEO