Exosomal Chaperones and miRNAs in Gliomagenesis: State-of-Art and Theranostics Perspectives

Gliomas have poor prognosis no matter the treatment applied, remaining an unmet clinical need. As background for a substantial change in this situation, this review will focus on the following points: (i) the steady progress in establishing the role of molecular chaperones in carcinogenesis; (ii) the recent advances in the knowledge of miRNAs in regulating gene expression, including genes involved in carcinogenesis and genes encoding chaperones; and (iii) the findings about exosomes and their cargo released by tumor cells. We would like to trigger a discussion about the involvement of exosomal chaperones and miRNAs in gliomagenesis. Chaperones may be either targets for therapy, due to their tumor-promoting activity, or therapeutic agents, due to their antitumor growth activity. Thus, chaperones may well represent a Janus-faced approach against tumors. This review focuses on extracellular chaperones as part of exosomes’ cargo, because of their potential as a new tool for the diagnosis and management of gliomas. Moreover, since exosomes transport chaperones and miRNAs (the latter possibly related to chaperone gene expression in the recipient cell), and probably deliver their cargo in the recipient cells, a new area of investigation is now open, which is bound to generate significant advances in the understanding and treatment of gliomas.

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Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment ?

10.20944/preprints201907.0081.v1 ◽

2019 ◽

Author(s):

Seul-Ki Choi ◽

Heejin Kam ◽

Kye-Young Kim ◽

Suk In Park ◽

Yun-Sil Lee

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Cancer Treatment ◽

Poor Prognosis ◽

Treatment Resistance ◽

Therapeutic Agents ◽

Heat Shock Protein 27 ◽

Cytoskeletal Remodeling ◽

Protein Chaperone

Heat shock protein 27 (HSP27), induced by heat shock, environmental, and pathophysiological stressors, is a multi-dimensional protein that acts as a protein chaperone and an antioxidant. HSP27 plays a major role in the inhibition of apoptosis and actin cytoskeletal remodeling. HSP27 is upregulated in many cancers and is associated with poor prognosis, as well as treatment resistance whereby cells are protected from therapeutic agents that normally induce apoptosis. This review highlights the most recent findings and role of HSP27 in cancer, as well as strategies for using HSP27 inhibitors for therapeutic purposes.

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Overexpression of chloroplast-targeted ferrochelatase 1 results in a genomes uncoupled chloroplast-to-nucleus retrograde signalling phenotype

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0401 ◽

2020 ◽

Vol 375 (1801) ◽

pp. 20190401 ◽

Cited By ~ 2

Author(s):

Mike T. Page ◽

Tania Garcia-Becerra ◽

Alison G. Smith ◽

Matthew J. Terry

Keyword(s):

Gene Expression ◽

Feedback Inhibition ◽

Nuclear Gene ◽

Signalling Pathway ◽

Chloroplast Genes ◽

Nuclear Gene Expression ◽

Retrograde Signalling ◽

Genes Encoding ◽

Retrograde Signal

Chloroplast development requires communication between the progenitor plastids and the nucleus, where most of the genes encoding chloroplast proteins reside. Retrograde signals from the chloroplast to the nucleus control the expression of many of these genes, but the signalling pathway is poorly understood. Tetrapyrroles have been strongly implicated as mediators of this signal with the current hypothesis being that haem produced by the activity of ferrochelatase 1 (FC1) is required to promote nuclear gene expression. We have tested this hypothesis by overexpressing FC1 and specifically targeting it to either chloroplasts or mitochondria, two possible locations for this enzyme. Our results show that targeting of FC1 to chloroplasts results in increased expression of the nuclear-encoded chloroplast genes GUN4 , CA1 , HEMA1 , LHCB2.1, CHLH after treatment with Norflurazon (NF) and that this increase correlates to FC1 gene expression and haem production measured by feedback inhibition of protochlorophyllide synthesis. Targeting FC1 to mitochondria did not enhance the expression of nuclear-encoded chloroplast genes after NF treatment. The overexpression of FC1 also increased nuclear gene expression in the absence of NF treatment, demonstrating that this pathway is operational in the absence of a stress treatment. Our results therefore support the hypothesis that haem synthesis is a promotive chloroplast-to-nucleus retrograde signal. However, not all FC1 overexpression lines enhanced nuclear gene expression, suggesting there is still a lot we do not understand about the role of FC1 in this signalling pathway. This article is part of the theme issue ‘Retrograde signalling from endosymbiotic organelles’.

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Correlation between Bacillus subtilis scoC Phenotype and Gene Expression Determined Using Microarrays for Transcriptome Analysis

Journal of Bacteriology ◽

10.1128/jb.183.24.7329-7340.2001 ◽

2001 ◽

Vol 183 (24) ◽

pp. 7329-7340 ◽

Cited By ~ 43

Author(s):

Robert Caldwell ◽

Ron Sapolsky ◽

Walter Weyler ◽

Randal R. Maile ◽

Stuart C. Causey ◽

...

Keyword(s):

Gene Expression ◽

Bacillus Subtilis ◽

Expression Patterns ◽

Global Scale ◽

Complete Sequence ◽

Dna Arrays ◽

Genome Wide ◽

Genes Encoding ◽

Nucleoside Metabolism

ABSTRACT The availability of the complete sequence of the Bacillus subtilis chromosome (F. Kunst et al., Nature 390:249–256, 1997) makes possible the construction of genome-wide DNA arrays and the study of this organism on a global scale. Because we have a long-standing interest in the effects of scoC on late-stage developmental phenomena as they relate toaprE expression, we studied the genome-wide effects of ascoC null mutant with the goal of furthering the understanding of the role of scoC in growth and developmental processes. In the present work we compared the expression patterns of isogenic B. subtilis strains, one of which carries a null mutation in the scoC locus (scoC4). The results obtained indicate thatscoC regulates, either directly or indirectly, the expression of at least 560 genes in the B. subtilisgenome. ScoC appeared to repress as well as activate gene expression. Changes in expression were observed in genes encoding transport and binding proteins, those involved in amino acid, carbohydrate, and nucleotide and/or nucleoside metabolism, and those associated with motility, sporulation, and adaptation to atypical conditions. Changes in gene expression were also observed for transcriptional regulators, along with sigma factors, regulatory phosphatases and kinases, and members of sensor regulator systems. In this report, we discuss some of the phenotypes associated with the scoCmutant in light of the transcriptome changes observed.

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Increased IGFBP7 Expression Correlates with Poor Prognosis and Immune Infiltration in Gastric Cancer: An Integrated Bioinformatics Analysis

10.21203/rs.3.rs-33369/v1 ◽

2020 ◽

Author(s):

Qiaoyun Zhao ◽

Rulin Zhao ◽

Conghua Song ◽

Huan Wang ◽

Jianfang Rong ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Poor Prognosis ◽

Bioinformatics Analysis ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Biological Processes ◽

Coexpressed Genes

Abstract Background Insulin-like growth factor binding protein-7 (IGFBP7) contributes to multiple biological processes in various tumors. However, the role of IGFBP7 in gastric cancer (GC) is still undetermined. The study aims to explore the role of IGFBP7 in GC via an integrated bioinformatics analysis.Methods IGFBP7 expression levels in GC and its normal gastric tissues were analyzed using multiple databases, including the Tumor Immune Estimation Resource (TIMER), Oncomine, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The methylation analysis was conducted with MEXPRESS, UALCAN and Xena online tools. The survival analysis was conducted using the Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Coexpressed genes of IGFBP7 were selected with the cBioPortal tool and enrichment analysis was conducted with the clusterProfiler package in R software. Gene set enrichment analysis (GSEA) was performed to explore the IGFBP7-related biological processes involved in GC. Correlations between IGFBP7 and immune cell infiltrates were analyzed using the TIMER database.Results IGFBP7 expression was significantly upregulated in GC and correlated with stage, grade, tumor status and Helicobacter pylori infection. High IGFBP7 expression and low IGFBP7 methylation levels were significantly associated with short survival of patients with GC. Univariate and multivariate analyses revealed that IGFBP7 was an independent risk factor for GC. The coexpressed genes LHFPL6, SEPTIN4, HSPB2, LAYN and GGT5 predicted unfavorable outcomes of GC. Enrichment analysis showed that the coexpressed genes were involved in extracellular matrix (ECM)-related processes. GSEA indicated that IGFBP7 was positively related to ECM and inflammation-related pathways. TIMER analysis indicated that the IGFBP7 expression level was strongly correlated with genes related to various infiltrating immune cells in GC, especially with gene markers of tumor associated macrophages (TAMs).Conclusions We demonstrate that increased IGFBP7 expression correlates with poor prognosis and immune cell infiltration in GC. IGFBP7 might be a potential biomarker for the diagnosis and targeted therapy for GC.

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High expression of CD52 predicts poor prognosis of cytogenetic normal acute myeloid leukemia

10.21203/rs.2.22823/v1 ◽

2020 ◽

Author(s):

Ping Cai ◽

Wenzhi Cai ◽

Xiaoyu Xu ◽

xiaofei Yang ◽

yemin Wang ◽

...

Keyword(s):

Gene Expression ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Leukemia Cell ◽

Dna Demethylation ◽

Rank Test ◽

Log Rank Test ◽

High Level ◽

Acute Myeloid

Abstract Background: The prognosis of cytogenetic normal acute myeloid leukemia (CN-AML) varies. Finding new biomarkers affecting the prognosis of these patients may bring a new strategy for precise classification and treatment. CD52 play a significant role in chronic lymphocytic leukemia (CLL). However, the potential role of CD52 in CN-AML remains largely elusive. Methods: We analyzed the prognostic role of different expression levels of CD52 in 58 CN-AML from The Cancer Genome Atlas (TCGA) dataset and validate these results with 345 CN-AML patients from Gene Expression Omnibus (GEO) dataset. Results: CN-AML patients with high CD52 mRNA expression have a poorer prognosis compared to low CD52 expression ( event-free survival [EFS], P =0.056; overall survival [OS], P=0.043; log-rank test) and the results was verified by GSE12417 (OS, P=0.0197; log-rank test) and GSE71014 (OS, P=0.0197; log-rank test). Hematopoietic stem cell transplantation (HSCT) may improve prognosis of patients with CD52 high . Multivariate cox regression analysis show that the expression level of CD52 (HR=1.503; 95%CI:1.158-1.949 ; P=0.002) was a prognostic factor independent of age (HR=3.045; 95%CI:1.524-6.086; P=0.002) and FLT3 mutation status (HR=2.219; 95%CI:1.123-4.382; P=0.022). CD52 gene expression show a predictive effect on EFS (1-year survival- area under the curve [AUC]:0.685, 2-year survival-AUC:0.752) and OS (1-year survival-AUC: 0.717, 2-year survival-AUC:0.770). Besides, we also found that there is a significant negative correlation between CD52 mRNA expression and DNA methylation . CD52 DNA demethylation may responsible for the high level of CD52 mRNA. Functional enrichment analysis of differentially expressed genes in CD52 high and CD52 low suggests that leukemia cell adhesion-related pathways may be associated with poor prognosis in CD52 high patients . Conclusions: CD52 gene mRNA overexpression is an independent adverse prognostic factor for CN-AML, which could be reversed by HSCT. CD52 DNA demethylation may responsible for the high level of CD52 mRNA. The poor prognosis of patients with CD52 high may involves in leukemia cell adhesion-related pathways. Whether CD52 monoclonal antibodies play a role in high risk patients need further research.

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Role of microRNAs in Renal Parenchymal Diseases—A New Dimension

10.20944/preprints201803.0129.v1 ◽

2018 ◽

Author(s):

Saeed Kamran Shaffi ◽

David Galas ◽

Alton Etheridge ◽

Christos Argyropoulos

Keyword(s):

Gene Expression ◽

Normal Development ◽

Therapeutic Targets ◽

Therapeutic Agents ◽

Renal Development ◽

Renal Repair ◽

Eukaryotic Organisms

Since their discovery in 1993, numerous microRNAs (miRNAs) have been identified in humans and other eukaryotic organisms, and their role as key regulators of gene expression is still being elucidated. It is now known that miRNAs not only play a central role in the processes that ensure normal development and physiology, but they are often dysregulated in various diseases. In this review, we present an overview of the role of miRNAs in normal renal development and physiology, in maladaptive renal repair after injury, and in the pathogenesis of renal parenchymal diseases. In addition, we describe methods used for their detection and their potential as therapeutic targets. Continued research on renal miRNAs will undoubtedly improve our understanding of diseases affecting the kidneys and may also lead to new therapeutic agents.

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Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment?

Cancers ◽

10.3390/cancers11081195 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1195 ◽

Cited By ~ 24

Author(s):

Choi ◽

Kam ◽

Kim ◽

Park ◽

Lee

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Poor Prognosis ◽

Treatment Resistance ◽

Therapeutic Agents ◽

Heat Shock Protein 27 ◽

Functional Protein ◽

Cytoskeletal Remodeling ◽

Protein Chaperone

Heat shock protein 27 (HSP27), induced by heat shock, environmental, and pathophysiological stressors, is a multi-functional protein that acts as a protein chaperone and an antioxidant. HSP27 plays a significant role in the inhibition of apoptosis and actin cytoskeletal remodeling. HSP27 is upregulated in many cancers and is associated with a poor prognosis, as well as treatment resistance, whereby cells are protected from therapeutic agents that normally induce apoptosis. This review highlights the most recent findings and role of HSP27 in cancer, as well as the strategies for using HSP27 inhibitors for therapeutic purposes.

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Grr1-dependent Inactivation of Mth1 Mediates Glucose-induced Dissociation of Rgt1 from HXT Gene Promoters

Molecular Biology of the Cell ◽

10.1091/mbc.e03-03-0135 ◽

2003 ◽

Vol 14 (8) ◽

pp. 3230-3241 ◽

Cited By ~ 110

Author(s):

Karin M. Flick ◽

Nathalie Spielewoy ◽

Tatyana I. Kalashnikova ◽

Marisela Guaderrama ◽

Qianzheng Zhu ◽

...

Keyword(s):

Gene Expression ◽

Budding Yeast ◽

Transcriptional Repressor ◽

Gene Promoters ◽

Negative Regulators ◽

Dependent Inactivation ◽

Genes Encoding ◽

F Box Protein

In budding yeast, HXT genes encoding hexose permeases are induced by glucose via a mechanism in which the F box protein Grr1 antagonizes activity of the transcriptional repressor Rgt1. Neither the mechanism of Rgt1 inactivation nor the role of Grr1 in that process has been understood. We show that glucose promotes phosphorylation of Rgt1 and its dissociation from HXT gene promoters. This cascade of events is dependent upon the F-box protein Grr1. Inactivation of Rgt1 is sufficient to explain the requirement for Grr1 but does not involve Rgt1 proteolysis or ubiquitination. We show that inactivation of Mth1 and Std1, known negative regulators of HXT gene expression, leads to the hyperphosphorylation of Rgt1 and its dissociation from HXT promoters even in the absence of glucose. Furthermore, inactivation of Mth1 and Std1 bypasses the requirement for Grr1 for induction of these events, suggesting they are targets for inactivation by Grr1. Consistent with that proposal, Mth1 is rapidly eliminated in response to glucose via a mechanism that requires Grr1. Based upon these data, we propose that glucose acts via Grr1 to promote the degradation of Mth1. Degradation of Mth1 leads to phosphorylation and dissociation of Rgt1 from HXT promoters, thereby activating HXT gene expression.

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Iron and Fur Regulation in Vibrio cholerae and the Role of Fur in Virulence

Infection and Immunity ◽

10.1128/iai.73.12.8167-8178.2005 ◽

2005 ◽

Vol 73 (12) ◽

pp. 8167-8178 ◽

Cited By ~ 125

Author(s):

Alexandra R. Mey ◽

Elizabeth E. Wyckoff ◽

Vanamala Kanukurthy ◽

Carolyn R. Fisher ◽

Shelley M. Payne

Keyword(s):

Gene Expression ◽

Vibrio Cholerae ◽

Iron Acquisition ◽

Bacterial Species ◽

Regulation Of Gene Expression ◽

Transport Systems ◽

Infant Mouse ◽

Genes Encoding ◽

Regulatory Functions

ABSTRACT Regulation of iron uptake and utilization is critical for bacterial growth and for prevention of iron toxicity. In many bacterial species, this regulation depends on the iron-responsive master regulator Fur. In this study we report the effects of iron and Fur on gene expression in Vibrio cholerae. We show that Fur has both positive and negative regulatory functions, and we demonstrate Fur-independent regulation of gene expression by iron. Nearly all of the known iron acquisition genes were repressed by Fur under iron-replete conditions. In addition, genes for two newly identified iron transport systems, Feo and Fbp, were found to be negatively regulated by iron and Fur. Other genes identified in this study as being induced in low iron and in the fur mutant include those encoding superoxide dismutase (sodA), fumarate dehydratase (fumC), bacterioferritin (bfr), bacterioferritin-associated ferredoxin (bfd), and multiple genes of unknown function. Several genes encoding iron-containing proteins were repressed in low iron and in the fur mutant, possibly reflecting the need to reserve available iron for the most critical functions. Also repressed in the fur mutant, but independently of iron, were genes located in the V. cholerae pathogenicity island, encoding the toxin-coregulated pilus (TCP), and genes within the V. cholerae mega-integron. The fur mutant exhibited very weak autoagglutination, indicating a possible defect in expression or assembly of the TCP, a major virulence factor of V. cholerae. Consistent with this observation, the fur mutant competed poorly with its wild-type parental strain for colonization of the infant mouse gut.

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Regulation of ABCA1 and ABCG1 gene expression in the intraabdominal adipose tissue

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20166203283 ◽

2016 ◽

Vol 62 (3) ◽

pp. 283-289 ◽

Cited By ~ 2

Author(s):

V.V. Miroshnikova ◽

A.A. Panteleeva ◽

E.A. Bazhenova ◽

E.P. Demina ◽

T.S. Usenko ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Cholesterol Metabolism ◽

Nuclear Factor ◽

Specific Expression ◽

Protein Levels ◽

Expression Of Genes ◽

Genes Encoding ◽

And Control

Tissue specific expression of genes encoding cholesterol transporters ABCA1 and ABCG1 as well as genes encoding the most important transcriptional regulators of adipogenesis – LXRa, LXRb, PPARg and RORa has been investigated in intraabdominal adipose tissue (IAT) samples.A direct correlation between the content of ABCA1 and ABCG1 proteins with RORa protein level (r=0.480, p<0.05; r=0.435, p<0.05, respectively) suggests the role of the transcription factor RORa in the regulation of IAT ABCA1 and ABCG1 protein levels. ABCA1 and ABCG1 gene expression positively correlated with obesity indicators such as body mass index (BMI) (r=0.522, p=0.004; r=0.594, p=0.001, respectively) and waist circumference (r=0.403, p=0.033; r=0.474, p=0.013, respectively). The development of obesity is associated with decreased IAT levels of RORa and LXRb mRNA (p=0.016 and p=0.002, respectively). These data suggest that the nuclear factor RORa can play a significant role in the regulation of cholesterol metabolism and control IAT expression of ABCA1 and ABCG1, while the level of IAT LXRb gene expression may be an important factor associated with the development of obesity.

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