Expression data from UMUC3 cells transduced with non-targeted shRNA and shRNA specific to AGL
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE73456 | GEO | 2015/09/26
SECONDARY ACCESSION(S): PRJNA297052
REPOSITORIES: GEO
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Project description:Background: HAS2 is a member of the gene family encoding hyaluronan synthase 2 (HAS2), which can generate high-molecular-weight hyaluronan (HMW-HA). Our previous study identified HAS2 as a candidate gene for susceptibility to adult asthma. However, little is known if HAS2 dysfunction affects airway remodeling and steroid insensivity. In this study, we clarified the dysfunction of Has2 triggering severe airway remodeling and steroid insensitivity in a murine model of asthma. Methods: Ovalbumin (OVA) was used to induce eosinophilic airway inflammation and airway remodeling in Has2 heterozygous deficient (Has2+/−) mice and their wild-type (WT) littermates. Lung tissue histology, bronchoalveolar lavage fluid cell counting, quantitative PCR, HA size analysis, multiplex cytokines and chemokines analysis, RNA sequencing, anti IL-17 neutralization experiment were performed. Results: After chronic OVA stimulation, Has2+/− (Has2+/--OVA) mice showed significant decrease of Has2 mRNA expression levels, HMW-HA, HA-binding protein, and TGF-β. Has2+/--OVA mice demonstrated increased eosinophilic airway inflammation, goblet cell hyperplasia, and IL-17 levels. RNA sequencing demonstrated downregulation of EIF2 signaling pathways, TGF-β signaling pathways, and heat shock proteins with Th17 bias in Has2+/--OVA mice. Combined treatment with anti IL-17 antibody and dexamethasone reduce steroid insensitivity in Has2+/--OVA mice Conclusions: Has2 attenuation worsen eosinophilic airway inflammation, airway remodeling, and steroid insensitivity. This severe intractable phenotype might be induced by impairment of TGF-β signaling and ER stress response related signaling. These data highlight that HAS2 and HMW-HA are important for controlling intractable eosinophilic airway inflammation and remodeling, and could potentially be exploited for therapeutic benefit to asthma patients.
2022-01-26 | GSE181966 | GEO
Project description:Amylo-alpha-1-6-glucosidase-4-alpha-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Inactivating germline mutations lead to glycogen storage disease III (GSDIII). AGL was found to be a tumor suppressor in xenograft models of bladder cancer (BC) and low levels of expression in BC were associated with poor patient prognosis. However, the impact of AGL levels in normal tissues on susceptibility to carcinogenesis is unknown. We address this gap by developing a full body/germline AGL knock-out (AGL-FBKO) that recapitulates biochemical and histological features of GSDIII. AGL-FBKO mice exposed to N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) had higher BC incidence at several time points following exposure, compared to wild type littermates (AGL-FBWT). To determine if this increased BC prevalence was due to decreased expression of AGL in the urothelium, we derived a urothelium specific conditional AGL knock-out (AGL-cKO) mouse driven by a Uroplakin II-Cre/loxP system. BBN experiments with these mice revealed AGL-cKO had higher BC incidence than mice without AGL knock-out (AGL-cWT). RNA-sequencing revealed that tumors from AGL-FBKO had 19 differentially expressed genes compared to AGL-FBWT mice. An “AGL Loss” gene signature was developed and found to successfully stratify normal and tumor samples in two BC patient datasets. These results support the role of AGL as a tumor suppressor. Our work suggests that evaluating AGL expression levels, or AGL KO gene signature scores, in normal urothelium may serve as a predictor for increased risk of BC development in individuals with carcinogenic exposures, such as smoking.
2020-03-31 | GSE113158 | GEO
Project description:Background: HAS2 is a member of the gene family encoding hyaluronan synthase 2 (HAS2) which can generate high molecular weight hyaluronan (HMW-HA). Although we previously reported that HAS2 is a novel candidate gene for susceptibility to adult asthma., little is known about whether HAS2 dysfunction affect eosinophilic airway inflammation. Objective: We therefore hypothesized that attenuation of HAS2 will enhance eosinophilic airway inflammation. Methods: C57BL/6 wild type (WT) mice, Has2 heterozygous deficient (Has2+/−) mice were used in eosinophilic airway inflammation model which induced by ovalbumin (OVA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to detect Has2 and HA binding protein mRNA expression levels. Lung tissue and lavage fluid (BALF) were analyzed for inflammation and various cytokines and chemokines. Airway resistance was measured using forced oscillation technique. gene expression analyses were also performed to elucidate further pathogenesis. Results: The expression levels of Has2 mRNA was significantly decreased in OVA stimulated Has2+/− (Has2+/−-OVA) mice. Has2+/−-OVA mice also displayed significant reduce of CD44, and TGF-beta1 mRNA expression. BALF eosinophil number, levels of various Th2 cytokines and chemokines in BALF, and airway responsiveness were significantly increased in Has2+/−-OVA mice compared with similarly treated WT mice. ILK Signaling and PKA signaling were downregulated significantly more in Has2+/−-OVA mice compared with similarly treated WT mice. Conclusions: Has2 dysfunction induce more intense allergic eosinophilic airway inflammation and increase of airway hyper responsiveness with impairment of HAS2-CD44-TGF-beta signaling. Modulating HAS2 signaling might provide novel therapeutic targets for intractable bronchial asthma patients.
2022-04-04 | GSE148161 | GEO
Project description:Tumor microenvironment with distinctive cell types and a complex extracellular matrix has a tremendous effect on cancer progression. In the present study we investigated the effects of proinflammatory (M1) and immunosuppressive (M2) macrophages on melanoma cell hyaluronan (HA) metabolism and inflammatory response. M1 macrophages stimulated the formation of a thick pericellular HA matrix in melanoma cells, and the overall HA synthesis was increased due to upregulation of HA synthases (HAS) 1 and 2. HAS2 silencing reversed the effect of M1 CM (conditioned medium) on pericellular HA coat formation, similarly as the chemical inhibitors for TNFR (R-7050), IKK2 (IKK16) and MEK (U0126). RNA sequencing analysis indicated that several inflammation related genes (IL1, IL6, CXCL6) were highly upregulated in M1 CM treated melanoma cells. Gene set enrichment analysis identified that genes related to inflammatory response and TNFα signaling via NF-κB are enriched in M1 CM treated cells. Our results indicate that the activation of MEK and TNFR-NF-κB signaling leads to HAS2 upregulation, while MEK signaling pathway is not involved in cytokine upregulation. Furthermore, HAS2 silencing downmodulated the M1 CM-induced cytokine expression. Our results indicate that proinflammatory macrophages induce an inflammatory response in melanoma cells, where HAS2 upregulation associates with a protumor inflammatory gene signature.
2022-04-26 | GSE178744 | GEO
Project description:Aims: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human induced pluripotent stem cells-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to downregulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirm that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and upregulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in has2os and degradation of the endothelial glycocalyx. Finally, we identify that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions: Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
2023-04-30 | GSE216453 | GEO
Project description:Aims: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human induced pluripotent stem cells-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to downregulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirm that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and upregulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in has2os and degradation of the endothelial glycocalyx. Finally, we identify that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions: Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
2023-04-30 | GSE216452 | GEO
Project description:At diagnosis approximately 75% of bladder urothelial carcinomas are non muscle invasive bladder cancers (Ta, T1 and Tis), 20% are muscle invasive bladder cancer (T2-T4) and 5% are already metastatic. Non muscle invasive bladder cancers are characterized by tumor recurrence in 60% to 85% of cases and, therefore, long-term followup is needed. The current standard methods to detect and monitor bladder cancer are cystoscopy and cytology. Cystoscopy is an invasive method and cytology is hampered by low sensitivity, especially for low grade tumors. So there is need to develop reliable and noninvasive methods to detect and predict bladder cancer biological behavior. So we have performed high density oligonucleotide microarray for discovery of new molecular markers to diagnose and predict the outcome of bladder cancer. Under an ethical guideline of Chhatrapati Shahuji Maharaj Medical University, India histologically confirmed seven bladder cancer patients were recruited from Department of Urology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India. Total RNA was extracted from tumor biopsies and hybridized on affymetrix Human Gene ST 1.1 array to determine differentially expressed genes in urinary bladder cancer with muscle invasion in comparison of normal human urinary bladder.
2012-02-22 | E-GEOD-23732 | biostudies-arrayexpress
Project description:Hepatic fibrosis remains a significant clinical challenge due to ineffective treatments. 4-methylumbelliferone (4MU), a hyaluronic acid (HA) synthesis inhibitor, has proven safe in phase one clinical trials. In this study, we aimed to ameliorate liver fibrosis by inhibiting HA synthesis. We compared two groups of mice with CCl4-induced fibrosis, treated with 4-methylumbelliferone (4MU) and hyaluronan synthase 2 (HAS2) targeting siRNA (siHAS2). The administration of 4MU and siHAS2 significantly reduced collagen and HA deposition, as well as biochemical markers of hepatic damage induced by repeated CCl4 injections. The transcriptomic analysis revealed converging pathways associated with downstream HA signalling. 4MU- and siHAS2-treated fibrotic livers shared 405 upregulated and 628 downregulated genes. These genes were associated with xenobiotic and cholesterol metabolism, mitosis, endoplasmic reticulum stress, RNA processing, and myeloid cell migration. The functional annotation of differentially expressed genes (DEGs) in siHAS2-treated mice revealed attenuation of extracellular matrix-associated pathways. In comparison, in the 4MU-treated group, DEGs were related to lipid and bile metabolism pathways and cell cycle. These findings confirm that HAS2 is an important pharmacological target for suppressing hepatic fibrosis using siRNA.
2023-08-30 | GSE241894 | GEO
Project description:We profile gene expression upon circHIPK3 KD in two bladder cancer cell lines UMUC3 and J82
2021-10-01 | GSE148824 | GEO
Project description:This study aimed to identify the genetic signatures associated with disease prognosis in bladder cancer. We used 165 primary bladder cancer samples, 23 recurrent non-muscle invasive tumor tissues, 58 normal looking bladder mucosae surrounding cancer and 10 normal bladder mucosae for microarray analysis. Hierarchical clustering was used to stratify the prognosis-related gene classifiers. For validation, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) of top-ranked 14 genes was performed. On unsupervised hierarchical clustering using prognosis related gene-classifier, tumors were divided into 2 groups. The high risk gene signatures had significantly poor prognosis compared to low risk gene signatures (P<0.001 by the log-rank test, respectively). The prognosis-related gene classifiers correlated significantly with recurrence of non-muscle invasive bladder cancer (hazard ratio, 4.09; 95% confidence interval [CI], 1.94 to 8.64; P<0.001), and progression (hazard ratio, 23.68; 95% confidence interval [CI], 4.91 to 114.30; P<0.001), cancer-specific survival (hazard ratio, 29.25; 95% confidence interval [CI], 3.47 to 246.98; P=0.002) and overall survival (hazard ratio, 23.33; 95% confidence interval [CI], 4.97 to 109.50; P<0.001) of muscle invasive bladder cancer (p < 0.001, respectively). No patient with non-muscle invasive bladder cancer experienced cancer progression in low risk gene signature group. Prognosis-related gene classifiers validated by RT- PCR showed identical results. Prognosis related gene-classifiers provided strong predictive value for disease outcome. These gene classifiers could assist in selecting patients who might benefit from more aggressive therapeutic intervention or surveillance. Keywords: Gene expression, Bladder cancer, Prognosis 165 primary bladder cancer samples and 23 recurrent non-muscle invasive tumor tissues from 14 patients were taken in the Chungbuk National University Hospital. Only histologically verified transitional cell carcinoma samples were selected. Simultaneously 58 normal looking bladder mucosae surrounding cancer were obtained during the operation, which were histologically confirmed normal. Also, 10 normal bladder mucosae were obtained from patients with benign disease. The normal controls were determined to be free of cancer after revealing no malignant cells on urine cytology and no observable bladder cancer on cystoscopic examination during operation for their diseases, and were histologically reconfirmed normal.
2010-05-28 | E-GEOD-13507 | biostudies-arrayexpress