Transcriptome analysis of SH-SY5Y neuroblastoma cells treated with copper and copper chelators (Dextran-Catechin - DC, and Tetraethylenepentamine pentahydrochloride - TEPA) in the presence or absence of interferon gamma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE155031 | GEO | 2020/07/28
REPOSITORIES: GEO
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Project description:Transcriptome analysis of SH-SY5Y neuroblastoma cells treated with copper and copper chelators (Dextran-Catechin - DC, and Tetraethylenepentamine pentahydrochloride - TEPA) in the presence or absence of interferon gamma
| PRJNA648963 | ENA
Project description:Iron-deficiency affects 500 million people, yet the molecular role of iron in gene expression remains poorly characterized. Moreover, the alterations in global gene expression after iron chelation remains unclear and are important to assess for understanding the molecular pathology of iron-deficiency and the biological effects of iron chelators. We assessed the effect on whole genome gene expression of two iron chelators (desferrioxamine and 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone) that have markedly different permeability properties. Sixteen genes were significantly regulated by both chelators, while a further 50 genes were regulated by either ligand. Most of the genes identified in this study have not been previously described to be iron-regulated and are important for understanding the molecular and cellular effects of iron-deficiency.
2010-02-28 | GSE17832 | GEO
Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.
2022-03-31 | MSV000089180 | MassIVE
Project description:The molecular role of iron in gene expression remains poorly characterized. Moreover, the alterations in global gene expression after iron chelation remains unclear and are important to assess for understanding the molecular pathology of iron-depletion and the biological effects of iron chelators. We assessed the effect on whole genome gene expression of two iron chelators (desferrioxamine and Dp44mT). These studies are important for understanding the molecular and cellular effects of iron-depletion.
2011-12-31 | GSE26920 | GEO
Project description:Programmed death ligand-1 (PD-L1) is a well-known transmembrane protein, which antibodies present effective clinical therapy in multiple human cancers. However, the function of tumor cell-intrinsic PD-L1 and its related mechanism in breast cancer remains incompletely studied. Programmed death ligand 1 (PD-L1) on the membrane of tumor cells strengthens tumor immune escape. Tumor cell-intrinsic PD-L1 is also involved in tumorigenesis and development, but the mechanism in regulating PD-L1 expression remains incompletely studied. Here, we report a novel mechanism for PD-L1 that can be induced by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, promoting breast cancer growth. Overexpression of PD-L1 increases breast cancer proliferation in vitro and in vivo. Transcriptomic analysis also reveals that PD-L1 plays a critical role in cancer development. Furthermore, we find that the expression of PD-L1 is positively associated with HBXIP in breast cancer clinical tissues as well as in cell lines, PD-L1 and HBXIP expression have higher levels in tumor. Mechanistically, HBXIP predominantly stimulates the promoter activity of PD-L1 through coactivating transcription factor ETS2. Especially, HBXIP induced PD-L1 acetylation with the acetyltransferase p300 at lysine 270 (K270), enhancing PD-L1 protein stability. Functionally, depletion of HBXIP markedly attenuates PD-L1-induced breast tumor growth in vitro and in vivo. Moreover, aspirin decreased breast cancer growth via targeting PD-L1 and HBXIP. Taken together, our results extend a new mechanism of PD-L1 functions, expound non-immune effects of PD-L1 and imply broader uses for PD-L1 as a target in breast cancer therapy.
2022-02-02 | GSE158696 | GEO
Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.
2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress
Project description:Cancer cells express high levels of PD-L1, a ligand of the PD-1 receptor on T cells, allowing tumors to suppress T cell activity 1-3. Clinical trials utilizing monoclonal antibodies that disrupt the PD-1/PD-L1 immune checkpoint have yielded remarkable results, with PD-1 immunotherapy approved as a first-line therapy for human lung cancer patients 4-6. Despite significant progress in targeting this pathway, the mechanisms through which PD-L1 is upregulated in non-small cell lung cancer (NSCLC) and other tumor types remain incompletely understood. Here we used CRISPR-based screening to identify regulators of PDL1 in human lung cancer cells, revealing potent induction of PD-L1 levels upon disruption of the heme biosynthesis pathway. Impairment of heme production activates the integrated stress response (ISR), allowing bypass of inhibitory upstream open reading frames in the PD-L1 5¢ UTR, resulting in enhanced PD-L1 translation and suppression of anti-tumor immunity. We further demonstrated that ISR-dependent translation of PD-L1 requires the translation initiation factor EIF5B. EIF5B overexpression, which is frequent in human lung cancers and is associated with poor prognosis, is sufficient to induce PD-L1. These findings uncover a new mechanism of immune checkpoint activation and suggest novel targets for therapeutic intervention.
2020-02-01 | GSE129968 | GEO
Project description:Iron and copper are important environmental nutrients for plant growth. However, the molecular mechanisms of both iron and copper signaling that integrate the two pathways remain poorly understood. The Arabidopsis thaliana high affinity copper transporter COPT5, is a tonoplast localized permease involved in copper remobilization. Here, a global expression microarray analysis of the copt5 mutant points out the induction of iron deficiency responses, including NATURAL RESISTANCE-ASSOCIATED MACROPHAGE PROTEIN 4 (NRAMP4), a tonoplast-localized iron transporter. The copper requirement in iron perception and uptake from the media becomes more evident in the double nramp3nramp4 mutant, unable to remobilize iron from vacuoles, that is highly sensitive to copper deficiency. Furthermore, COPT5 expression is altered under iron deficiency and the copt5 mutant is sensitive to iron deficiency and is unable to perceive iron in the media under copper deficiency. Noteworthy, iron deficiency post-transcriptionally restraints the copper-dependent superoxide dismutase protein levels and the subsequent activity. As a consequence of its increased iron deficiency responses, the copt5 mutant present lower levels of both copper- and iron-dependent superoxide dismutase activities. Moreover, the copt5 mutant mobilizes faster its iron storage pools and presents higher levels of iron in cotyledons and seeds. These results underline the importance of internal metal pools in the understanding of copper and iron deficiency responses and their crosstalk that are critical for governing proper plant development in response to combined metal scarcities in soils.
2017-05-30 | GSE91044 | GEO
Project description:Iron-deficiency affects 500 million people, yet the molecular role of iron in gene expression remains poorly characterized. Moreover, the alterations in global gene expression after iron chelation remains unclear and are important to assess for understanding the molecular pathology of iron-deficiency and the biological effects of iron chelators. We assessed the effect on whole genome gene expression of two iron chelators (desferrioxamine and 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone) that have markedly different permeability properties. Sixteen genes were significantly regulated by both chelators, while a further 50 genes were regulated by either ligand. Most of the genes identified in this study have not been previously described to be iron-regulated and are important for understanding the molecular and cellular effects of iron-deficiency. The MCF-7 cells were incubated with either control medium or this medium containing DFO (250 µM) or 311 (25 µM) for 24 h at 37oC. These concentrations were used since our previous studies demonstrated that under these conditions these chelators lead to up-regulation of iron-responsive genes such as the TfR1 after this incubation time.8 Moreover, the higher concentration of DFO was implemented due to its limited ability to permeate cell membranes. Total RNA was isolated from cells in 1 mL of TRIzol® reagent (Invitrogen). Samples were then prepared and hybridized to the Human Genome U133 Plus 2.0 430 2.0. The human GeneChip® U133 Plus 2.0 consists of greater than 47,000 transcripts and variants from over 38,500 well characterized human genes. On completion of hybridization and washing, microarray chips were scanned with the Affymetrix GeneChip® Scanner 3000 (Affymetrix).
2010-03-09 | E-GEOD-17832 | biostudies-arrayexpress
Project description:Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Positive cytology in ascites was a significant poor prognostic factor in ovarian cancer. Microarray profiles of cytology-positive cases showed significant correlations with Gene Ontology terms related to immune system process. Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and positive cytology. PD-L1 expression on mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and upon co-culturing with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in human ovarian cancer tissue from ascites-cytology-positive or -negative patients.
2012-07-09 | E-GEOD-39204 | biostudies-arrayexpress