Human umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Kevin Becker
PROVIDER: E-GEOD-64839 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Human umbilical cord matrix mesenchymal stem cells suppress the growth of breast cancer by expression of tumor suppressor genes.
Ohta Naomi N Ishiguro Susumu S Kawabata Atsushi A Uppalapati Deepthi D Pyle Marla M Troyer Deryl D De Supriyo S Zhang Yongqing Y Becker Kevin G KG Tamura Masaaki M
PloS one 20150505 5
Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naïve UCMSC and those co ...[more]
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Project description:Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naïve UCMSC and those co-cultured with species-matched breast carcinoma cells. The analyses screened 17 differentially expressed genes that are commonly detected in both human and rat UCMSC. The comparison between the two sets of gene expression profiles identified two tumor suppressor genes, adipose-differentiation related protein (ADRP) and follistatin (FST), that were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species' breast carcinoma cells. Over-expression of FST, but not ADRP, in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. The growth of MDA-231 cells was also significantly lower when they were cultured in medium conditioned with FST, but not ADRP over-expressing human UCMSC. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-overexpressing human UCMSC significantly attenuated the tumor burden. These results suggest that FST may play an important role in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and also implies that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression. Rat UCMSC and Mat B III breast carcinoma cells were cultured indirectly for 48 hours using Transwell culture dish. Naïve rat UCMSC were cultured under same condition without the addition of carcinoma cells.
2015-08-06 | E-GEOD-64838 | biostudies-arrayexpress
Project description:Human and rat umbilical cord matrix mesenchymal stem cells (UCMSC) possess the ability to control the growth of breast carcinoma cells. Comparative analyses of two types of UCMSC suggest that rat UCMSC-dependent growth regulation is significantly stronger than that of human UCMSC. Their different tumoricidal abilities were clarified by analyzing gene expression profiles in the two types of UCMSC. Microarray analysis revealed differential gene expression between untreated naïve UCMSC and those co-cultured with species-matched breast carcinoma cells. The analyses screened 17 differentially expressed genes that are commonly detected in both human and rat UCMSC. The comparison between the two sets of gene expression profiles identified two tumor suppressor genes, adipose-differentiation related protein (ADRP) and follistatin (FST), that were specifically up-regulated in rat UCMSC, but down-regulated in human UCMSC when they were co-cultured with the corresponding species' breast carcinoma cells. Over-expression of FST, but not ADRP, in human UCMSC enhanced their ability to suppress the growth of MDA-231 cells. The growth of MDA-231 cells was also significantly lower when they were cultured in medium conditioned with FST, but not ADRP over-expressing human UCMSC. In the breast carcinoma lung metastasis model generated with MDA-231 cells, systemic treatment with FST-overexpressing human UCMSC significantly attenuated the tumor burden. These results suggest that FST may play an important role in exhibiting stronger tumoricidal ability in rat UCMSC than human UCMSC and also implies that human UCMSC can be transformed into stronger tumoricidal cells by enhancing tumor suppressor gene expression. Human UCMSC and MDA-231 breast carcinoma cells were cultured indirectly for 48 hours using Transwell culture dish. Naïve human UCMSC were cultured under same condition without the addition of carcinoma cells.
2015-08-06 | E-GEOD-64827 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-01-08 | E-GEOD-62376 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-08-07 | E-GEOD-71850 | biostudies-arrayexpress
Project description:Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to AlzheimerM-bM-^@M-^Ys disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. Keywords: Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; AlzheimerM-bM-^@M-^Ys disease A mild physical-TBI was induced using a concussive head trauma device described previously (Milman et al., 2005; Zohar et al., 2003). Briefly, mice were lightly anesthetized (Isoflurane) and placed under the weight-drop concussive head trauma instrument. The device consisted of a metal tube (inner diameter 13 mm), placed vertically over the mouse head. A metal weight (30 g) was dropped from the top of the tube (80 cm) and struck the skull at the right side temporal area between the corner of the eye and the ear. A sponge supported the head, allowing some antero-posterior motion without any rotational head movement at the moment of the impact. Experimental conditions used to create a mild low-level blast-TBI and the subsequent model characterization, have been described in detail elsewhere (Rubovitch et al., 2011). In brief, mice were anaesthetized with a combination of ketamine (100 mg/kg) and xylazine (10 mg/kg). Once the animals were fully anaesthetized they were placed at a defined distance from a detonation source, in this case 7 meters. Pressure sensors were used to measure the explosion shock wave pressure (PSI) generated by the detonation (Free-Field ICPM-BM-. Blast Pressure Sensor; PCB Piezoelectronics, Depew, NY, USA, Model 137). At 7 meters from the source of the detonation, the animals were exposed to a maximum of a 2.5 PSI (17.2 kPa) pressure shock wave. Immediately after the induction of the injury, mice were placed back in their cages. Once the animals had recovered from the anesthesia, basic neurological assessments were undertaken to identify any acute neurological dysfunction. Only animals exhibiting no evidence of acute neurological damage post injury were subsequently used in further experiments. Sham treated mouse groups were treated identically; however, they were not exposed to physical- or blast-TBI. Mouse hippocampus tissues were randomly selected from the larger library of samples generated from the behavioral experiments and the numbers utilized in the gene expression study were as follows: sham, n = 5: physical-TBI, n = 4; blast-TBI, n = 7.
2013-03-18 | E-GEOD-44625 | biostudies-arrayexpress
Project description:Mitochondrial dysfunction is a common feature in neurodegeneration and aging. We identify mitochondrial dysfunction in xeroderma pigmentosum group A (XPA), a nucleotide excision DNA repair disorder with severe neurodegeneration, in silico and in vivo. XPA deficient cells show defective mitophagy with excessive cleavage of PINK1 and increased mitochondrial membrane potential. The mitochondrial abnormalities appear to be caused by decreased activation of the NAD+-SIRT1-PGC-1? axis triggered by hyperactivation of the DNA damage sensor PARP1. This phenotype is rescued by PARP1 inhibition or by supplementation with NAD+ precursors that also rescue the lifespan defect in xpa-1 nematodes. Importantly, this pathogenesis appears common to ataxia-telangiectasia and Cockayne syndrome, two other DNA repair disorders with neurodegeneration, but absent in XPC, a DNA repair disorder without neurodegeneration. Our findings reveal a novel nuclear-mitochondrial cross-talk that is critical for the maintenance of mitochondrial health. Mice carrying WT, or CX (Csa-/-/Xpa-/-) alleles in a C57BL/6 background were maintained under standard laboratory conditions and allowed free access to water and control casein pelleted diet (Research Diets D12450B). At 3 months of age, 3 replicates of each of the CX and WT mice were given subcutaneous interscapular injections of 500 mg of Nicotinamide riboside/kg body weight/day or the equivalent volume of saline for 14 consecutive days at 4:00 pm. On day 15, the mice were sacrificed and half of the cerebellum was harvested for purification of mitochondria, with the left half snap-frozen, homogenized, and aliquoted for RNA isolation. Total RNA extraction was done using a TRIzol Plus RNA purification kit as per manufacturer’s protocol. Quality and quantity of the total RNA was tested using the Agilent 2100 Bio-Analyzer and RNA 6000 nano kits. The RNA was labeled using the standard Illumina protocol and hybed overnight to Mouse Ref-8 Illumina arrays. The arrays were scanned using the Beadstation 500 X from Illumina.
2015-06-04 | E-GEOD-55485 | biostudies-arrayexpress
Project description:The prevention or delay of the onset of age-related diseases prolongs survival and improves quality of life while reducing the burden on the health care system. Activation of sirtuin 1 (SIRT1), an NAD+ deacetylase, improves metabolism and confers protection against physiological and cognitive disturbances in old age. SRT1720 is a specific SIRT1 activator that has health and lifespan benefits in adult mice fed a highfat diet. We found extension in lifespan, delayed onset of age-related metabolic diseases, and improved general health in mice fed a standard diet after SRT1720 supplementation. Inhibition of pro-inflammatory gene expression both in the liver and muscle of SRT1720-treated animals was noted. SRT1720 lowered phosphorylation of NF-κB pathway regulators in vitro only when SIRT1 was functionally present. Combined with our previous work, the current study further supports the beneficial effects of SRT1720 on health across the lifespan in mice. Groups of 28 week old male C57BL/6J mice were maintained on ad libitum AIN-93G SD diet, or an ad libitum AIN-93G diet supplemented with SRT1720 for the rest of their lives. SRT1720 was added at a dose of 1.33 g drug per kg of chow, formulated to provide daily doses of approximately 100 mg drug per kg bodyweight to the mice. 5 mice from each group were selected and RNA was extracted from both muscle and liver tissue using 1.0mm glass beads in a Precellys 24 Tissue Homogenizer and Qiagen RNeasy Mini Kits for Fibrous Tissue according to manufacturer's specifications. Quality and quantity of the total RNA was checked with the Agilent 2100 bioanalyzer using RNA 6000 Nano chips. RNA samples were labeled using the Illumina TotalPrep RNA Amplification Kit. In short, 0.5ug of total RNA was first converted into single-stranded cDNA with reverse transcriptase using an oligo-dT primer containing the T7 RNA polymerase promoter site and then copied to produce double-stranded cDNA molecules. The double stranded cDNA was cleaned and concentrated with the supplied columns and used in an overnight in-vitro transcription reaction where single-stranded RNA (cRNA) was generated and labeled by incorporation of biotin-16-UTP. Arrays were hybridized using a total of 0.75ug of biotin-labeled cRNA at 58 degrees C for 16 hours to Illumina's Sentrix MouseRef-8 v2 Expression BeadChips. Each BeadChip has ~24,000 well-annotated RefSeq transcripts with approximately 30-fold redundancy. The arrays were washed, blocked and the biotin labeled cRNA was detected by staining with streptavidin-Cy3. Arrays were scanned at a resolution of 0.8um using the Beadstation 500 X from Illumina and the data was extracted using the Illumina GenomeStudio software(v1.6.0). Any spots at or below the background were filtered out using an Illumina detection p value of 0.02 and above. The natural log of all remaining scores were used to find the avg and std of each array and the z-score normalization was calculated and presented below. Z-score = (raw value - avg)/std.
2014-12-20 | E-GEOD-50987 | biostudies-arrayexpress
Project description:Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans. Key words: Sirtuins, lifespan, healthspan, osteoporosis, muscle wasting, inflammation Groups of 28 week old male C57BL6/J mice were maintained for the rest of their lives or until sacrifice on either an ad libitum AIN-93G SD diet, an ad libitum AIN-93G diet supplemented with SRT2104 or a caloric restricted AIN-93G diet consisting of 60% of what the ad lib animals ate. SRT2104 was added at a dose of 1.33 g drug per kg of chow, formulated to provide daily doses of approximately 100 mg drug per kg bodyweight to the mice. 5 mice from each group were selected after 41 weeks and RNA was extracted from both muscle and liver tissue using 1.0mm glass beads in a Precellys 24 Tissue Homogenizer and Qiagen RNeasy Mini Kits for Fibrous Tissue according to manufacturer's specifications. Quality and quantity of the total RNA was checked with the Agilent 2100 bioanalyzer using RNA 6000 Nano chips. RNA samples were labeled using the Illumina TotalPrep RNA Amplification Kit. In short, 0.5ug of total RNA was first converted into single-stranded cDNA with reverse transcriptase using an oligo-dT primer containing the T7 RNA polymerase promoter site and then copied to produce double-stranded cDNA molecules. The double stranded cDNA was cleaned and concentrated with the supplied columns and used in an overnight in-vitro transcription reaction where single-stranded RNA (cRNA) was generated and labeled by incorporation of biotin-16-UTP. Arrays were hybridized using a total of 0.75ug of biotin-labeled cRNA at 58 degrees C for 16 hours to Illumina's Sentrix MouseRef-8 v2 Expression BeadChips. Each BeadChip has ~24,000 well-annotated RefSeq transcripts with approximately 30-fold redundancy. The arrays were washed, blocked and the biotin labeled cRNA was detected by staining with streptavidin-Cy3. Arrays were scanned at a resolution of 0.8um using the Beadstation 500 X from Illumina and the data was extracted using the Illumina GenomeStudio software(v1.6.0). Any spots at or below the background were filtered out using an Illumina detection p value of 0.02 and above. The natural log of all remaining scores were used to find the avg and std of each array and the z-score normalization was calculated and presented below. Z-score = (raw value - avg)/std.
2014-09-22 | E-GEOD-49000 | biostudies-arrayexpress
Project description:Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in the genes encoding the DNA repair proteins CSA or CSB. Csbm/m mice were given a high-fat, caloric-restricted or resveratrol-supplemented diet. The high-fat diet rescued the phenotype of Csbm/m mice at the metabolic, transcriptomic and behavioral levels. Additional analysis suggests that the premature aging seen in CS mice, nematodes and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet; and β-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB is able to displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS. 4-month-old mice, WT and Csbm/m on a C57BL/6 background, were fed a standard AIN-93G diet (SD; carbohydrate:protein:fat ratio of 64:19:17 percent of kcal) ad libitum or at 40% CR, a SD supplemented with 100 mg/kgchow resveratrol ad libitum, or a high-fat diet ad libitum consisting of AIN-93G with 60% of calories from fat, primarily hydrogenated coconut oil (HFD; carbohydrate:protein:fat ratio of 16:23:61). Each group was on the specified diet for 8 months, after which the mice were sacrificed and the cerebellum was removed. For nicotinamide treatments, 4- or 18-month-old WT and Csbm/m mice were given daily injections of nicotinamide riboside (NR) (500 mg/kg/d, ip) or saline for one week, after which the mice were sacrificed and the cerebellum was removed. RNA was extracted from the cerebellums of all mice using Trizol, and RNA quality and quantity were tested using an Agilent 2100 BioAnalyzer with RNA 6000 nano chips. RNA was labeled using the standard Illumina protocol for Illumina TotalPrep RNA Amplification Kit. Labeled RNA was hybridized to Illumina's Sentrix MouseRef-8 v2 Expression BeadChips (Illumina, San Diego, CA) overnight and washed, stained and scanned the next day.
2014-12-22 | E-GEOD-62194 | biostudies-arrayexpress
Project description:Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The recent identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA that yield bioactive peptides. Here we report the identification of a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA -c) that regulates insulin sensitivity and metabolic homeostasis. MOTS-c is detected in various tissues and in circulation in an age-dependent manner. Its primary target organ appears to be the skeletal muscle and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, causing a significant accumulation of AICAR levels concomitantly with AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may be more actively engaged in regulating metabolic homeostasis than previously recognized, through the production of peptides encoded within its genome that act at the cellular and organismal level. Human embryonic kidney cells (HEK293 cell line) were cultured in 10-cm dishes in 7 mL of phenol-free DMEM supplemented with 10% FBS and incubated with water (controls) or the 16-amino-acid peptide mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c, 10 uM) for 4 or 72 hours prior to RNA extraction.
2015-03-07 | E-GEOD-65068 | biostudies-arrayexpress