scholarly journals Activation of the miR-371/372/373 miRNA Cluster Enhances Oncogenicity and Drug Resistance in Oral Carcinoma Cells

2020 ◽  
Vol 21 (24) ◽  
pp. 9442
Author(s):  
Shu-Chun Lin ◽  
Hsiao-Li Wu ◽  
Li-Yin Yeh ◽  
Cheng-Chieh Yang ◽  
Shou-Yen Kao ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Transcriptional Activation ◽  
Mirna Cluster ◽  
Human Stem Cells ◽  
Oncogenic Potential ◽  
Synergistic Activation ◽  
Cisplatin Sensitivity ◽  
The Individual ◽  
Cell Subclones

Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated deaths worldwide. Family members in miR-371/372/373 miRNA cluster, which is localized at human chromosome 19q13.4, are co-expressed in both human stem cells and malignancies. The individual miRNA in this cluster are also involved in modulating the pathogenesis of malignancies as either oncogenes or suppressors. The 19q13 region is frequently gained in head and neck cancers. High expression of miR-372 and miR-373 are survival predictors for OSCC. However, the role of the miR-371/372/373 cluster in oral carcinogenesis remains to be fully investigated. We use the clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system to establish OSCC cell subclones that had the miR-371/372/373 cluster deleted. In addition, further subclones were established that had the promoter of this cluster deleted. Concordant silencing in SAS cells of miR-371/372/373 decreased oncogenic potential, increased cisplatin sensitivity, activated p53, and upregulated the expression of Bad and DKK1. We also employed the CRISPR/dCas9 synergistic activation mediator system, which allowed robust transcriptional activation of the whole miR-371/372/373 cistron. Upregulation of endogenous miR-371/372/372 expression increased both oncogenicity and drug resistance. These were accompanied by a slight activation of AKT, β-catenin, and Src. This study identifies the oncogenic role of the miR-371/372/373 cluster in OSCC. Using CRISPR based strategy can be a powerful paradigm that will provide mechanistic insights into miRNA cluster functionality, which will also likely help the development of targeting options for malignancies.

scholarly journals Role of Known Molecular Markers of Resistance in the Antimalarial Potency of Piperaquine and Dihydroartemisinin In Vitro

2009 ◽  
Vol 53 (4) ◽  
pp. 1362-1366 ◽  
Author(s):  
Sant Muangnoicharoen ◽  
David J. Johnson ◽  
Sornchai Looareesuwan ◽  
Srivicha Krudsood ◽  
Stephen A. Ward
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Artemisinin Combination Therapy ◽  
Parasite Line ◽  
South American ◽  
Resistance Markers ◽  
Positive Correlations ◽  
The Individual

ABSTRACT Using a range of laboratory-adapted and genetically modified Plasmodium falciparum parasite isolates, we investigated the interaction between dihydroartemisinin and piperaquine (PIP), the individual components of an artemisinin combination therapy currently under development, in addition to the role of known drug resistance genes in parasite susceptibility in vitro. All but one parasite line investigated displayed an interaction of dihydroartemisinin and PIP that was antagonistic, although the degree of antagonism was isolate dependent. In terms of resistance markers, the pfcrt haplotypes CVIET and SVMNT were positively associated with reduced sensitivity to PIP, with parasites carrying the South American CQR (SVMNT) allele being generally less sensitive than CVIET parasites. Parasites carrying the CQS (CVMNK) allele displayed a further increase in PIP sensitivity compared with CVIET and SVMNT parasites. Our data indicate that PIP sensitivity was not affected by pfmdr1 sequence status, despite positive correlations between the structurally related compound amodiaquine and pfmdr1 mutations in other studies. In contrast, neither the pfcrt nor pfmdr1 sequence status had any significant impact on susceptibility to dihydroartemisinin.

scholarly journals Upregulation of MiR-340-5p Reverses Cisplatin Sensitivity by Inhibiting the Expression of CDK6 in HepG2 Cells

2021 ◽  
Vol 69 (2) ◽  
pp. 57-66
Author(s):  
Sha Tian ◽  
Zhuo Liu ◽  
Qing Zhou ◽  
Ruoxia Wu ◽  
Xiaodi Huang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Liver Cancer ◽  
Hepg2 Cells ◽  
Luciferase Reporter ◽  
Cycle Arrest ◽  
Cisplatin Sensitivity ◽  
New Ideas ◽  
Lower Drug ◽  
Dual Luciferase Reporter Assay

Cisplatin (CDDP) has been successfully used in chemotherapy for liver cancer. However, the development of CDDP resistance in HepG2 cells usually leads to relapse and a worsening prognosis. MiR-340-5p has attracted much attention because of its ability to affect cell resistance. This project is intended to explore the role of miR-340-5p and CDK6 in CDDP-R HepG2 cells and provide new ideas for the treatment of liver cancer. A dual-luciferase reporter assay was used to confirm the targeting relationship between miR-340-5p and CDK6. We constructed a CDDP-resistant model of HepG2 cells to examine the effect of miR-340-5p on the drug sensitivity of HepG2 cells. CDDP-R HepG2 cells were transfected with miR-340-5p overexpression plasmid and CDK6 silencing plasmid. QRT-PCR was used to detect the expression of miR-340-5p and CDK6. A western blot was performed to determine the expression of CDK6, CyclinD1, and CyclinD2. CCK-8, flow cytometry, TUNEL and Clonogenic assays were also carried out to detect CDDP-R HepG2 cells. There is a targeting relationship between miR-340-5p and CDK6. The drug resistance of CDDP-R HepG2 cells was significantly higher than that of CDDP-S HepG2 cells. CDDP-R HepG2 cells transfected with both miR-340-5p overexpressing plasmid and CDK6 silencing plasmid showed a lower proliferation ability, cell cycle arrest in the G0/G1 phase, and lower drug resistance compared with single CDDP-R HepG2 cells. Overexpression of miR-340-5p aggravated CDDP-R HepG2 cells' apoptosis and inhibited cell viability. Overexpression of miR-340-5p could reverse the sensitivity of HepG2 cells to CDDP by inhibiting the expression of CDK6 in HepG2 cells.

scholarly journals Rationale for Targeting BCL6 in MLL-Rearranged B-ALL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1239-1239
Author(s):  
Lai N Chan ◽  
Christian Hurtz ◽  
Huimin Geng ◽  
Erica Ballabio ◽  
Gang Xiao ◽  
...  
Keyword(s):  
Drug Resistance ◽  
B Cell ◽  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Research Funding ◽  
Pharmacological Inhibition ◽  
Equity Ownership ◽  
Bcl6 Expression ◽  
Bh3 Mimetic

Background and significance: MLL-gene rearrangements occur in ~10% of B-cell acute lymphoblastic leukemia (B-ALL) and 70% of infant B-ALL and define a group of patients with dismal outcomes. MLL belongs to the family of histone methyltransferases and plays a critical role in maintaining hematopoietic stem cells (Jude et al. 2007). Analyzing gene expression data from 207 children with high-risk ALL, we found that BCL6 is a predictor of poor clinical outcome in B-ALL, particularly in cases with MLL rearrangements. Thus, while the mechanisms of drug-resistance in MLL-rearranged B-ALL are largely unknown, we studied here a potential role of BCL6 in promoting the aggressive and refractory phenotype in this subtype of B-ALL. Results: Immunohistochemical staining of bone marrow biopsies from 10 of 11 MLL-rearranged B-ALL samples studied revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug-resistance in B-ALL (Duy et al. Nature 2011). Our genetic and ChIP-seq analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and upregulated BCL6 expression. While oncogenic MLL-fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to upregulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL-rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL-rearranged B-ALL patient samples. Oncogenic MLL-fusions strongly induced transcriptional activation of the pro-apoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small-molecule (FX1) BCL6-inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL-rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL-fusions and identified BCL6 as a novel target for the treatment of MLL-rearranged B-ALL. Discussion: Pharmacological inhibition of BCL6 using a retro-inverso peptide inhibitor (RI-BPI) compromised MLL-rearranged B-ALL leukemia-initiation and subverted vincristine-resistance. A central mechanistic aspect of BCL6-function in MLL-rearranged B-ALL involves transcriptional repression of the pro-apoptotic BH3-only molecule Bim (BCL2L11). Profiling for BH3-only proteins in various B-ALL subtypes revealed that MLL-rearranged B-ALL is associated with increased expression of the pro-apoptotic protein BIM (Benito et al. 2015). ABT-199 (venetoclax) is a BH3-mimetic that disrupts the interaction between BCL2 and BIM, leading to BIM release and induction of apoptosis. Previous studies have found that MLL-rearranged leukemia cells are sensitive to the BCL2 inhibitor ABT-199. Besides BCL2, we here identified BCL6 as a central antagonist of pro-apoptotic BIM function in MLL-rearranged B-ALL cells. In genetic experiments, we showed that oncogenic MLL-fusions strongly activated BCL2L11 transcription reinforcing the notion that constitutively high Bim expression levels represents an important and selective vulnerability in MLL-rearranged B-ALL. Both BCL2 and BCL6 represent crucial antagonists of BIM in MLL-rearranged B-ALL, BCL2 mediating BIM-sequestration and BCL6 being required for transcriptional repression of BIM. In support of this scenario, peptide (RI-BPI) and small molecule (FX1) inhibitors of BCL6 strongly synergized with blockade of BCL2-mediated BIM sequestration (ABT-199) in killing MLL-rearranged B-ALL cells. Figure 1 Disclosures Armstrong: AstraZeneca: Research Funding; Epizyme, Inc.: Consultancy, Equity Ownership; Imago Biosciences, Inc.: Consultancy, Equity Ownership; Cyteir Therapeutics: Consultancy, Equity Ownership; Janssen: Research Funding; Novartis: Research Funding; Accent Therapeutics: Consultancy, Equity Ownership; Mana Therapeutics: Consultancy, Equity Ownership; C4 Therapeutics: Consultancy, Equity Ownership; Syros Pharmaceuticals: Consultancy, Equity Ownership; OxStem Oncology: Consultancy, Equity Ownership. Melnick:Janssen: Research Funding; Constellation: Consultancy; Epizyme: Consultancy. Milne:OxStem Ltd.: Equity Ownership.

Role of molecular chaperones in steroid receptor action

2004 ◽  
Vol 40 ◽  
pp. 41-58 ◽  
Author(s):  
William B Pratt ◽  
Mario D Galigniana ◽  
Yoshihiro Morishima ◽  
Patrick J M Murphy
Keyword(s):  
Transcriptional Activation ◽  
Protein Trafficking ◽  
Steroid Receptors ◽  
Transcriptional Regulatory ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Receptor Action ◽  
Binding Cleft ◽  
Hsp 90

Unliganded steroid receptors are assembled into heterocomplexes with heat-shock protein (hsp) 90 by a multiprotein chaperone machinery. In addition to binding the receptors at the chaperone site, hsp90 binds cofactors at other sites that are part of the assembly machinery, as well as immunophilins that connect the assembled receptor-hsp90 heterocomplexes to a protein trafficking pathway. The hsp90-/hsp70-based chaperone machinery interacts with the unliganded glucocorticoid receptor to open the steroid-binding cleft to access by a steroid, and the machinery interacts in very dynamic fashion with the liganded, transformed receptor to facilitate its translocation along microtubular highways to the nucleus. In the nucleus, the chaperone machinery interacts with the receptor in transcriptional regulatory complexes after hormone dissociation to release the receptor and terminate transcriptional activation. By forming heterocomplexes with hsp90, the chaperone machinery stabilizes the receptor to degradation by the ubiquitin-proteasome pathway of proteolysis.

School Success and School Engagement of Immigrant Children and Adolescents

2013 ◽  
Vol 18 (2) ◽  
pp. 126-135 ◽  
Author(s):  
Frosso Motti-Stefanidi ◽  
Ann S. Masten
Keyword(s):  
Academic Achievement ◽  
Academic Success ◽  
Children And Adolescents ◽  
School Engagement ◽  
School Success ◽  
Immigrant Children ◽  
Integrative Model ◽  
High Stakes ◽  
The Individual

Academic achievement in immigrant children and adolescents is an indicator of current and future adaptive success. Since the future of immigrant youths is inextricably linked to that of the receiving society, the success of their trajectory through school becomes a high stakes issue both for the individual and society. The present article focuses on school success in immigrant children and adolescents, and the role of school engagement in accounting for individual and group differences in academic achievement from the perspective of a multilevel integrative model of immigrant youths’ adaptation ( Motti-Stefanidi, Berry, Chryssochoou, Sam, & Phinney, 2012 ). Drawing on this conceptual framework, school success is examined in developmental and acculturative context, taking into account multiple levels of analysis. Findings suggest that for both immigrant and nonimmigrant youths the relationship between school engagement and school success is bidirectional, each influencing over time the other. Evidence regarding potential moderating and mediating roles of school engagement for the academic success of immigrant youths also is evaluated.

Methods to unravel the role of HDAC10 in autophagy-related drug resistance

2015 ◽  
Vol 227 (06/07) ◽  
Author(s):  
J Fabian ◽  
J Ridinger ◽  
O Witt ◽  
I Oehme
Keyword(s):  
Drug Resistance ◽  
Related Drug

Role of Transcriptional Read-Through in PRE Activity in Drosophila melanogaster

Acta Naturae ◽  
2016 ◽  
Vol 8 (2) ◽  
pp. 79-86 ◽  
Author(s):  
P. V. Elizar’ev ◽  
D. V. Lomaev ◽  
D. A. Chetverina ◽  
P. G. Georgiev ◽  
M. M. Erokhin
Keyword(s):  
Dna Sequences ◽  
Cell Types ◽  
Transcription Terminator ◽  
Response Elements ◽  
Polycomb Response Elements ◽  
The Individual ◽  
Multicellular Organisms ◽  
Different Cell Types ◽  
Main Factor

Maintenance of the individual patterns of gene expression in different cell types is required for the differentiation and development of multicellular organisms. Expression of many genes is controlled by Polycomb (PcG) and Trithorax (TrxG) group proteins that act through association with chromatin. PcG/TrxG are assembled on the DNA sequences termed PREs (Polycomb Response Elements), the activity of which can be modulated and switched from repression to activation. In this study, we analyzed the influence of transcriptional read-through on PRE activity switch mediated by the yeast activator GAL4. We show that a transcription terminator inserted between the promoter and PRE doesnt prevent switching of PRE activity from repression to activation. We demonstrate that, independently of PRE orientation, high levels of transcription fail to dislodge PcG/TrxG proteins from PRE in the absence of a terminator. Thus, transcription is not the main factor required for PRE activity switch.

УКРАЇНОЗНАВЧИЙ ОСВІТНІЙ ЧИННИК В УМОВАХ СУЧАСНОЇ УКРАЇНСЬКОЇ МАСОВОЇ КУЛЬТУРИ

2019 ◽  
pp. 22-29
Author(s):  
Н. В. Фрадкіна
Keyword(s):  
Mass Culture ◽  
Personal Development ◽  
Negative Impact ◽  
Educational Process ◽  
Point Of View ◽  
Character Trait ◽  
Main Task ◽  
Leading Role ◽  
The Individual

The purpose and tasks of the work are to analyze the contemporary Ukrainian mass culture in terms of its value and humanistic components, as well as the importance of cultural studies and Ukrainian studies in educational disciplines for the formation of a holistic worldview of modern youth.Analysis of research and publications. Scientists repeatedly turned to the problems of the role of spirituality in the formation of society and its culture. This problem is highlighted in the publications by O. Losev, V. Lytvyn, D. Likhachev, S. Avierintsev, M. Zakovych, I. Stepanenko and E. Kostyshyn.Experts see the main negative impact of mass culture on the quality approach, which determines mass culture through the market, because mass culture, from our point of view, is everything that is sold and used in mass demand.One of the most interesting studies on this issue was the work by the representatives of Frankfurt School M. Horkheimer and T. Adorno «Dialectics of Enlightenment» (1947), devoted to a detailed analysis of mass culture. Propaganda at all socio-cultural levels in the form is similar in both totalitarian and democratic countries. It is connected, according to the authors, with the direction of European enlightenment. The tendency to unify people is a manifestation of the influence of mass culture, from cinema to pop. Mass culture is a phenomenon whose existence is associated with commerce (accumulation in any form – this is the main feature of education), in general, the fact that it exists in this form is related to the direction of the history of civilization.Modern mass culture, with its externally attractive and easily assimilated ideas and symbols, appealing to the trends of modern fashion, becomes a standard of prestigious consumption, does not require intense reflection, allows you to relax, distract, not teach, but entertains, preaches hedonism as the main spiritual value. And as a consequence, there are socio-cultural risks: an active rejection of other people, which leads to the formation of indifference; cruelty as a character trait; increase of violent and mercenary crime; increase in the number of alcohol and drug addicts; anti-patriotism; indifference to the values of the family and as a result of social orphanhood and prostitution.Conclusions, perspectives of research. Thus, we can conclude that modern Ukrainian education is predominantly formed by the values of mass culture. Namely, according to the «Dialectic» by Horkheimer and Adorno, «semi-enlightenment becomes an objective spirit» of our modern society.It is concluded that only high-quality education can create the opposite of the onset of mass culture and the destruction of spirituality in our society. It is proved that only by realizing the importance of cultivating disciplines in the educational process and the spiritual upbringing of the nation, through educational reforms, humanitarian knowledge will gradually return to student audiences.Formation of youth occurs under the influence of social environment, culture, education and self-education. The optimal combination of these factors determines both the process of socialization itself and how successful it will be. In this context, one can see the leading role of education and upbringing. It turns out that the main task of modern education is to spread its influence on the development of spiritual culture of the individual, which eventually becomes a solid foundation for the formation of the individual. Such a subject requires both philosophical and humanitarian approaches in further integrated interdisciplinary research, since the availability of such research will provide the theoretical foundation for truly modern educational and personal development.

MEDIA SOCIALIZATION OF PERSONALITY IN THE CONTEXT OF INMUTATION IN THE MASS MEDIA

2021 ◽  
pp. 104-109
Author(s):  
Chernysh O.O.
Keyword(s):  
Mass Media ◽  
Negative Impact ◽  
Effective Interaction ◽  
Individual Characteristics ◽  
Media Culture ◽  
Active Growth ◽  
Media Space ◽  
The Media ◽  
The Individual

The urgency of the researched problem is connected with the growing role of mass media in modern conditions leads to change of values and transformation of identity of the person. The active growth of the role of the media, their influence on the formation and development of personality leads to the concept of “media socialization” and immutation in the media. The aim of the study is to outline the possibilities of the process of media socialization in the context of immutation in the media. The methods of our research are: analysis of pedagogical, psychological, literature, synthesis, comparison, generalization. The article analyzes the views of domestic and foreign scientists on the problem of immutation in the media and the transformation of the information space. In the context of the mass nature of the immutation of society, the concept of “media socialization” becomes relevant, which is the basis for reducing the negative impact of the media on the individual.The author identifies the lack of a thorough study of the concept of “media socialization” in modern scientific thought. Thus, media socialization is associated with the transformation of traditional means of socialization, and is to assimilate and reproduce the social experience of mankind with the help of new media.The article analyzes the essence of the concepts “media space”, “mass media” and “immutation”. The influence of mass media on the formation and development of the modern personality is described in detail.The study concluded that it is necessary to form a media culture of the individual, to establish safe and effective interaction of young people with the modern media system, the formation of media awareness, media literacy and media competence in accordance with age and individual characteristics for successful media socialization. The role of state bodies in solving the problem of media socialization of the individual was also determined. It is determined that the process of formation of media culture in youth should take place at the level of traditional institutions of socialization of the individual.The author sees the prospect of further research in a detailed analysis and study of the potential of educational institutions as an institution and a means of counteracting the mass nature of the immutation of society.Key words: immutation, media socialization, mass media, media space, information.

The Role of Threat and Economic Uncertainty in Support for Scottish Independence

2014 ◽  
Vol 23 (1) ◽  
pp. 103-124 ◽  
Author(s):  
Daniel Kopasker
Keyword(s):  
Economic Consequences ◽  
Perceived Threat ◽  
Constitutional Change ◽  
Lack Of Information ◽  
Economic Expectations ◽  
Scottish Independence ◽  
The Individual ◽  
The Impact ◽  
Levels Of Support

Existing research has consistently shown that perceptions of the potential economic consequences of Scottish independence are vital to levels of support for constitutional change. This paper attempts to investigate the mechanism by which expectations of the economic consequences of independence are formed. A hypothesised causal micro-level mechanism is tested that relates constitutional preferences to the existing skill investments of the individual. Evidence is presented that larger skill investments are associated with a greater likelihood of perceiving economic threats from independence. Additionally, greater perceived threat results in lower support for independence. The impact of uncertainty on both positive and negative economic expectations is also examined. While uncertainty has little effect on negative expectations, it significantly reduces the likelihood of those with positive expectations supporting independence. Overall, it appears that a general economy-wide threat is most significant, and it is conjectured that this stems a lack of information on macroeconomic governance credentials.

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