Filters
Technology
Platform
GSE20229
Homo sapiens
10 Downloadable Samples
Affymetrix Human Genome U95 Version 2 Array (hgu95av2)
Description
Post-translational regulation of the MYC Transcription Factor (TF), including its phosphorylation and ubiquitination, plays an important role in determining cell proliferation and apoptosis and has been implicated in tumorigenesis. Using a computational systems biology approach, followed by biochemical and functional validation, we have characterized the role of the STK38 kinase, an NDR family serine-threonine kinase, as a key modulator of MYC transcriptional activity in human B cells, affecting MYC protein stability in a signal-dependent fashion. Specifically, we show that in human B lymphoma ST486 cells STK38 is a key mediator of BCR pathway signaling, affecting MYC protein turnover and its phosphorylation at Ser62 in kinase-activity-dependent manner. STK38 inactivation abrogates apoptosis following BCR activation while its silencing mediates MYC protein degradation via canonical proteolytic pathways. This suggests that STK38 could provide an effective therapeutic target in MYC-dependent malignancies.
Publication Title
STK38 is a critical upstream regulator of MYC's oncogenic activity in human B-cell lymphoma.
Sample Metadata Fields
Cell line, Time
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Mouse lymphoma cells were co-cultured with endothelial cells in serum/cytokine-free condition. To identify specific genetic changes, we compared lymphoma cells cultured in medium containing 10% fetal bovine serum with lymphoma cells co-cultured with endothelial cells.
Publication Title
Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Hepatocellular carcinoma (HCC) is the second most common cause of cancer related death. NAFLD affects a large proportion of the US population. Its incidence and prevalence are increasing to epidemic proportions around the world and is known to increase the risk of HCC. We studied how intrahepatic lipids affect adaptive immunity and HCC development in different murine models of NASH and HCC. Linoleic acid, a fatty acid found in NAFLD caused a selective loss of hepatic CD4+ but not CD8+ T cells leading to accelerated hepatocarcinogenesis. CD4+ T cells were more dependent on oxidative phosphorylation for energy source than CD8+ T cells, and disruption of oxidative phosphorylation by linoleic acid caused more severe damage in CD4+ T cells leading to selective loss of these cells. In vivo blockade of ROS using n-acetylcysteine reversed the NASH-induced hepatic CD4+ T cell decrease and delayed NASH-promoted HCC. Our results provide a new link between lipid metabolism and impaired anti-tumor surveillance.
Publication Title
NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Dnmt3b is a DNA methytransferase which is an enzyme that methylated genomic DNA which contributes to genomic stability and transcriptional regulation.
Publication Title
Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
Illumina HiSeq 2500
Description
To inhibit INS expression, we used shRNA to target the INS promoter. We find that knocking down INS expression with such an shRNA targeting the INS promoter significantly affects expression of 259 genes. Overall design: mRNA profiles of EndoC ßH1 with or without shRNA targetting INS promoter were generated by deep sequencing, in triplicate, using Illumina Hiseq 2500.
Publication Title
<i>Insulin</i> promoter in human pancreatic β cells contacts diabetes susceptibility loci and regulates genes affecting insulin metabolism.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 55 Downloadable Samples
- NextSeq 500
Description
The Myc/Max heterodimer has crucial roles in normal cellular processes such as cell proliferation, metabolism, apoptosis, and differentiation, but its activity is often deregulated in a majority of human cancers. In an effort to explore alternative modes of Myc perturbation, we identified KI-MS2-008 as a small molecule that binds Max and modulates Myc-driven transcription, and in some cellular contexts, KI-MS2-008 treatment leads to a decrease in c-Myc protein levels. As the Myc/Max heterodimer controls many cellular processes, we expected that treatment with this small molecule would cause changes in the transcriptome. We found that treatment with 10 µM KI-MS2-008 resulted in global alterations in the transcriptome, mimicking direct Myc inactivation with doxycycline in P493-6, a B cell line with a Tet-Off system for c-Myc expression. We also discovered enrichment of various Myc target gene sets in the genes downregulated in response to KI-MS2-008 treatment in P493-6 cells. This trend was also observed in ST486 cells, but not in P3HR1 cells, which were chosen as non-engineered B cell lines that were sensitive and insensitive, respectively, toward KI-MS2-008 in cell viability assays. Overall design: RNA-seq characterizing three B cell lines: P493-6 (an engineered, KI-MS2-008 sensitive cell line), ST486 (a non-engineered, KI-MS2-008 sensitive cell line), and P3HR1 (a non-engineered, KI-MS2-008 insensitive cell line). P493-6 cells were treated with 0.1 µg/mL doxycycline, 1 µM KI-MS2-008, 10 µM KI-MS2-008, or 0.4% DMSO for 45 minutes or 8 hours. ST486 cells were treated with 1 µM KI-MS2-008, 10 µM KI-MS2-008 or 0.4% DMSO for 45 minutes or 8 hours. P3HR1 cells were treated with 10 µM KI-MS2-008 or 0.4% DMSO for 8 hours. 4 replicates were performed for each condition.
Publication Title
Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject, Time
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Purpose: Primary cutaneous squamous cell carcinoma (SCC) can be an invasive cancer in skin and has the potential to metastasize. We aimed to define the cancer related molecular changes that distinguish non-invasive from invasive SCC.
Publication Title
Gene expression profiling of the leading edge of cutaneous squamous cell carcinoma: IL-24-driven MMP-7.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 23 Downloadable Samples
- Affymetrix Human Genome U95 Version 2 Array (hgu95av2)
Description
Organ transplant recipients (OTRs) on Cyclosporine A (CSA) are prone to catastrophic cutaneous squamous cell carcinoma (SCC). Allograft-sparing, cancer-targeting systemic treatments are unavailable. We have shown increased risk for catastrophic SCC in OTRs via CSA-mediated induction of Interleukin-22 (IL-22). Herein, we found CSA drives SCC proliferation and tumor growth through IL-22 and JAK/STAT pathway induction. We in turn inhibited SCC growth with an FDA-approved JAK 1/2 inhibitor, Ruxolitinib. In human SCC cells, greatest proliferative response to IL-22 and CSA treatment occurred in non-metastasizing lines. IL-22 treatment upregulated JAK1 and STAT1/3 in A431 SCC cells. JAK/STAT pathway genes were highly expressed in tumors from a cohort of CSA-exposed OTRs, and in SCC with high risk for metastasis. Compared to immunocompetent SCC, genes associated with innate immunity, response to DNA damage and p53 regulation were differentially expressed in SCC from OTRs. In nude mice engrafted with human A431 cells, IL-22 and CSA treatment increased tumor growth and upregulated IL-22 receptor, JAK1 and STAT 1/3 expression. Ruxolitinib treatment significantly reduced tumor volume and reversed the accelerated tumor growth. CSA and IL-22 exacerbate aggressive behavior in SCC. Targeting the IL-22 axis via selective JAK/STAT inhibition may reduce the progression of aggressive SCC in OTRs, without compromising immunosuppression.
Publication Title
Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 21 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Background; Basal cell carcinoma (BCC) is the most common cancer in humans. The pathogenesis of BCC is associated with the sonic hedgehog (SHH) signaling pathway. Vismodegib, a smoothened inhibitor, that targets this pathway is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. Methods; We studied gene expression profiling of BCC tumour tissue coupled with laser capture microdissection to identify tumor specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. The expression of selected molecules was confirmed by quantitative RT-PCR (qRT-PCR) and by immunohistochemistry. The action of kinase inhibitors was examined on primary normal human epidermal keratinocytes. Results; We found a >250 fold change increase (false discovery rate <10-4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger staining of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Additionally, Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met, another receptor tyrosine kinase, inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 mRNA by approximately 60% and 20%, respectively (p<0.05). Conclusions; Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promotes keratinocyte proliferation. Furthermore, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients.
Publication Title
Identification of anaplastic lymphoma kinase as a potential therapeutic target in Basal Cell Carcinoma.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U95 Version 2 Array (hgu95av2)
Description
Zaire ebolavirus (ZEBOV) infections are associated with high lethality in primates. ZEBOV primarily targets mononuclear phagocytes, which are activated upon infection and secrete mediators believed to trigger initial stages of pathogenesis. The characterization of the responses of target cells to ZEBOV infection may therefore not only further understanding of pathogenesis but also suggest possible points of therapeutic intervention. Gene expression profiles of primary human macrophages exposed to ZEBOV were determined using DNA microarrays and quantitative PCR to gain insight into the cellular response immediately after cell entry. Significant changes in mRNA concentrations encoding for 88 cellular proteins were observed. Most of these proteins have not yet been implicated in ZEBOV infection. Some, however, are inflammatory mediators known to be elevated during the acute phase of disease in the blood of ZEBOV-infected humans. Interestingly, the cellular response occurred within the first hour of Ebola virion exposure, i.e. prior to virus gene expression. This observation supports the hypothesis that virion binding or entry mediated by the spike glycoprotein (GP1,2) is the primary stimulus for an initial response. Indeed, ZEBOV virions, LPS, and virus-like particles consisting of only the ZEBOV matrix protein VP40 and GP1,2 (VLPVP40-GP) triggered comparable responses in macrophages, including pro-inflammatory and pro-apoptotic signals. In contrast, VLPVP40 (particles lacking GP1,2) caused an aberrant response. Notably, some cellular interferon-inducible genes were upregulated six hours after exposure to virions and LPS, but not after exposure to VLPVP40-GP. This suggests that GP1,2 binding to macrophages plays an important role in the immediate cellular response.
Publication Title
Ebola virion attachment and entry into human macrophages profoundly effects early cellular gene expression.
Sample Metadata Fields
Disease, Disease stage, Subject
View Samples