Tumor metastasis and lack of NKG2D ligand (NKG2DL) expression are associated with poor prognosis in patients with colon cancer. Here we found that spironolactone (SPIR), an FDA-approved diuretic drug with a long-term safety profile, can upregulate NKG2DL expression in multiple colon cancer cell lines by activating the ATM-Chk2-mediated checkpoint pathway, which in turn enhances tumor elimination by natural killer cells. SPIR can also upregulate the expression of metastasis-suppressor genes TIMP2 and TIMP3, thereby reducing tumor cell invasiveness. Although SPIR is an aldosterone antagonist, its anti-tumor effects are independent of the mineralocorticoid receptor pathway. Instead, by screening the human nuclear hormone receptor siRNA library, we identify retinoid X receptor gamma (RXR gamma) as being indispensable for the anti-tumor functions of SPIR. Collectively, our results strongly support the use of SPIR or other RXR gamma-agonists with minimal side effects for colon cancer prevention and therapy.
Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXRγ activation.
Treatment
View SamplesG protein coupled receptor (GPCR) signalling covers three major mechanisms. GPCR agonist engagement allows for the G proteins to bind to the receptor leading to a classical downstream signalling cascade. The second mechanism is via the utilization of the ß-arrestin signalling molecule and thirdly via transactivation dependent signalling. GPCRs can transactivate protein tyrosine kinase receptors (PTKR) to activate respective downstream signalling intermediates. In the past decade GPCR transactivation dependent signalling was expanded to show transactivation of serine/threonine kinase receptors (S/TKR). Kinase receptor transactivation enormously broadens the GPCR signalling paradigm. This work utilizes next generation RNA-sequencing to study the contribution of transactivation dependent signalling to total protease activated receptor (PAR)-1 signalling. Transactivation, assessed as gene expression, accounted for 50 percent of the total genes regulated by thrombin acting through PAR-1 in human coronary artery smooth muscle cells. GPCR transactivation of PTKRs is approximately equally important as the transactivation of the S/TKR with 209 and 177 genes regulated respectively, via either signalling pathway. This work shows that genome wide studies can provide powerful insights into GPCR mediated signalling pathways Overall design: Human CASMCS cells were subject to various treatments: basal, thrombin, thrombin + SB, thrombin + AG and thrombin + SB + AG. Gene expression was studies after 30 minutes to assess genes that are differentially expressed by treat emnt with agonists and antagonists. The agonoists and antagonists are associated with transactivation of GPCRs and the gene expression results will help identify relevant genes.
RNA sequencing to determine the contribution of kinase receptor transactivation to G protein coupled receptor signalling in vascular smooth muscle cells.
Specimen part, Treatment, Subject
View SamplesPreeclampsia complicates more than 3% of all pregnancies in the United States and Europe. High-risk populations include women with diabetes, dyslipidemia, thrombotic disorders, hyperhomocysteinemia, hypertension, renal diseases, previous preeclampsia, twin pregnancies, and low socioeconomic status. In the latter case, the incidence may increase to 20% to 25%. Preeclampsia is a major cause of maternal and fetal morbidity and mortality. Preeclampsia is defined by systolic blood pressure of more than 140 mm Hg and diastolic blood pressure of more than 90 mm Hg after 20 weeks gestation in a previously normotensive patient, and new-onset proteinuria. Abnormal placentation associated with shallow trophoblast invasion (fetal cells from outer cell layer of the blastocyst) into endometrium (decidua) and improper spiral artery remodeling in the decidua are initial pathological steps.
Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia.
No sample metadata fields
View SamplesExpression data from 22 human myotubes (7 healthy controls, 4 Dysferlinopathy (DYSF), 4 Caveolinopathy 3 (CAV3), 4 Facioscapulohumeral muscular dystrophy(FSHD) and 3 Four and a half LIM 1 protein deficiency FHL1).cDNA microarray data showed that cyclin A1 levels are specifically elevated in FSHD vs. other muscular disorders such as CAV3, DYSF, FHL1 and healthy control. Data could be confirmed with RT-PCR and Western blot analysis showing up-regulated levels of cyclin A1 also on the protein level.
Altered expression of cyclin A 1 in muscle of patients with facioscapulohumeral muscle dystrophy (FSHD-1).
Age, Specimen part, Disease, Disease stage
View SamplesExpression analysis revealed that UBD is a down-stream element of Foxp3 in human activated regulatory CD4+ T cells (Treg).
UBD, a downstream element of FOXP3, allows the identification of LGALS3, a new marker of human regulatory T cells.
Specimen part
View SamplesBackground: Studies in mice have shown that PPAR is an important regulator of lipid metabolism in liver and a key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPAR in human liver. Here we set out to study the function of PPAR in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPAR agonist Wy14643.
The impact of PPARα activation on whole genome gene expression in human precision cut liver slices.
Sex, Specimen part, Treatment, Subject, Time
View SamplesLittle is known about the early transcriptional events in innate immune signaling in immature and tolerogenic monocyte-derived dendritic cells (DCs), the professional antigen-presenting cells of our immune system. TLR ligands usually induce a proinflammatory transcriptional response, whereas IL10 and/or dexamethasone induce a more tolerogenic phenotype.
MicroRNA genes preferentially expressed in dendritic cells contain sites for conserved transcription factor binding motifs in their promoters.
Specimen part
View SamplesGene expression profiling on IL-10-secreting and non-secreting murine Th1 cells, stimulated in the presence or absence of the Notch ligand Delta-like 4 (Dll4), was performed to identify transcription factors co-expressed with IL-10.
Role of Blimp-1 in programing Th effector cells into IL-10 producers.
Specimen part
View SamplesGENES ASSOCIATED WITH THE CELL CYCLE, LINEAGE COMMITMENT AND IMMUNOMODULATORY POTENTIAL DISCRIMINATE HUMAN POSTNATAL STEM CELLS OF DIFFERENT ORIGIN.
Functional differences between mesenchymal stem cell populations are reflected by their transcriptome.
No sample metadata fields
View SamplesIn this study we aimed to identify a baseline intrahepatic transcriptional signature associated with response in chronic hepatitis B patients treated with peginterferon-alfa-2a (peg-IFN) and adefovir.
An intrahepatic transcriptional signature of enhanced immune activity predicts response to peginterferon in chronic hepatitis B.
Specimen part, Disease, Disease stage
View Samples