scholarly journals TBIO-21. Lnc-TALC PROMOTES O6-METHYLGUANINE-DNA METHYLTRANSFERASE EXPRESSION VIA REGULATING THE C-MET PATHWAY BY COMPETITIVELY BINDING WITH miR-20b-3p

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii470-iii470
Author(s):  
Pengfei Wu ◽  
Jinquan Cai ◽  
Qun Chen
Keyword(s):  
Dna Methyltransferase ◽  
Noncoding Rnas ◽  
Therapeutic Resistance ◽  
Biological Processes ◽  
Promoter Regions ◽  
Methylguanine Dna Methyltransferase ◽  
Phosphorylated Akt ◽  
Clinical Benefits ◽  
Glioblastoma Recurrence

Abstract Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.

scholarly journals Impact of Temozolomide on Immune Response during Malignant Glioma Chemotherapy

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Sadhak Sengupta ◽  
Jaclyn Marrinan ◽  
Caroline Frishman ◽  
Prakash Sampath
Keyword(s):  
Immune Response ◽  
Malignant Glioma ◽  
Dna Methyltransferase ◽  
Opportunistic Infections ◽  
Immune Surveillance ◽  
Drug Resistant ◽  
Methylguanine Dna Methyltransferase ◽  
Drug Resistant Mutation ◽  
Resistant Mutation

Malignant glioma, or glioblastoma, is the most common and lethal form of brain tumor with a median survival time of 15 months. The established therapeutic regimen includes a tripartite therapy of surgical resection followed by radiation and temozolomide (TMZ) chemotherapy, concurrently with radiation and then as an adjuvant. TMZ, a DNA alkylating agent, is the most successful antiglioma drug and has added several months to the life expectancy of malignant glioma patients. However, TMZ is also responsible for inducing lymphopenia and myelosuppression in malignant glioma patients undergoing chemotherapy. Although TMZ-induced lymphopenia has been attributed to facilitate antitumor vaccination studies by inducing passive immune response, in general lymphopenic conditions have been associated with poor immune surveillance leading to opportunistic infections in glioma patients, as well as disrupting active antiglioma immune response by depleting both T and NK cells. Deletion of O6-methylguanine-DNA-methyltransferase (MGMT) activity, a DNA repair enzyme, by temozolomide has been determined to be the cause of lymphopenia. Drug-resistant mutation of the MGMT protein has been shown to render chemoprotection against TMZ. The immune modulating role of TMZ during glioma chemotherapy and possible mechanisms to establish a strong TMZ-resistant immune response have been discussed.

scholarly journals CpGislandEVO: A Database and Genome Browser for Comparative Evolutionary Genomics of CpG Islands

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Guillermo Barturen ◽  
Stefanie Geisen ◽  
Francisco Dios ◽  
E. J. Maarten Hamberg ◽  
Michael Hackenberg ◽  
...  
Keyword(s):  
Mammalian Species ◽  
Cpg Islands ◽  
Sequence Divergence ◽  
Aberrant Methylation ◽  
Biological Processes ◽  
Orthologous Genes ◽  
Promoter Regions ◽  
Nucleotide Substitutions ◽  
Health And Disease

Hypomethylated, CpG-rich DNA segments (CpG islands, CGIs) are epigenome markers involved in key biological processes. Aberrant methylation is implicated in the appearance of several disorders as cancer, immunodeficiency, or centromere instability. Furthermore, methylation differences at promoter regions between human and chimpanzee strongly associate with genes involved in neurological/psychological disorders and cancers. Therefore, the evolutionary comparative analyses of CGIs can provide insights on the functional role of these epigenome markers in both health and disease. Given the lack of specific tools, we developedCpGislandEVO. Briefly, we first compile a database of statistically significant CGIs for the best assembled mammalian genome sequences available to date. Second, by means of a coupled browser front-end, we focus on the CGIs overlapping orthologous genes extracted fromOrthoDB, thus ensuring the comparison between CGIs located on truly homologous genome segments. This allows comparing the main compositional features between homologous CGIs. Finally, to facilitate nucleotide comparisons, we lifted genome coordinates between assemblies from different species, which enables the analysis of sequence divergence by direct count of nucleotide substitutions and indels occurring between homologous CGIs. The resultingCpGislandEVOdatabase, linking together CGIs and single-cytosine DNA methylation data from several mammalian species, is freely available at our website.

scholarly journals Role of O6-methylguanine-DNA methyltransferase and p53 in response of neuroblastoma cells to an alkylating agent temozolomide

2018 ◽  
Vol 99 (1) ◽  
pp. 47-53
Author(s):  
R R Khusnutdinov ◽  
S V Boychuk
Keyword(s):  
Dna Methyltransferase ◽  
Alkylating Agent ◽  
Neuroblastoma Cells ◽  
Methylguanine Dna Methyltransferase

Цель. Изучить роль белка р53 и О6-метилгуанин-ДНК-метилтрансферазы в чувствительности клеток нейробластомы к действию темозоломида. Методы. Исследование проводили на клеточной линии нейробластомы SK.N.SH, культивируемой в среде DMEM с добавлением эмбриональной телячьей сыворотки и антибиотиков пенициллина-стрептомицина в стандартных условиях (37 °C и 5% СО2). Клетки инкубировали с алкилирующим агентом темозоломидом в течение 48-72 ч. В ряде случаев осуществляли преинкубацию клеток в течение 2 ч с О6-бензилгуанином (ингибитором О6-метилгуанин-ДНК-метилтрансферазы) или нутлином-3а (реактиватором р53). Пролиферативную активность оценивали с помощью системы многопараметрического анализа клеточных культур (RTCA iCELLigence), а также колориметрического MTS-теста. Экспрессию белков определяли методом иммуноблоттинга с использованием соответствующих моноклональных антител. Результаты. Реактивация белка р53 приводила к значительному снижению скорости пролиферации клеток линии SK.N.SH. Цитотоксический эффект данного препарата более выражен по сравнению с темозоломидом, считающимся препаратом выбора при проведении химиотерапии пациентам с мультиформной глиобластомой и нейробластомой. Ингибирование О6-метилгуанин-ДНК-метилтрансферазы также приводило к усилению цитотоксического эффекта темозоломида, тем не менее, цитотоксический эффект химиопрепарата был менее выраженным по сравнению с действием темозоломида на фоне реактивации белка р53. Вывод. Для оценки чувствительности клеток нейробластомы к действию алкилирующего препарата темозоломида функциональное состояние белка р53 в опухолевых клетках служит более важным прогностическим критерием по сравнению с уровнем экспрессии О6-метилгуанин-ДНК-метилтрансферазы; кроме того, реактивация белка р53 приводит к снижению скорости пролиферации клеток нейробластомы линии SK.N.SH и их гибели по механизму апоптоза.

scholarly journals The promising role of noncoding RNAs in cancer-associated fibroblasts: an overview of current status and future perspectives

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Zengli Fang ◽  
Jin Xu ◽  
Bo Zhang ◽  
Wei Wang ◽  
Jiang Liu ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Noncoding Rnas ◽  
Current Status ◽  
Cancer Therapies ◽  
Cancer Associated Fibroblasts ◽  
Biological Processes ◽  
Future Perspectives ◽  
Metabolic Characteristics ◽  
Complex Regulatory Network

AbstractAs the most important component of the stromal cell population in the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) are crucial players in tumor initiation and progression. The interaction between CAFs and tumor cells, as well as the resulting effect, is much greater than initially expected. Numerous studies have shown that noncoding RNAs (ncRNAs) play an irreplaceable role in this interplay, and related evidence continues to emerge and advance. Under the action of ncRNAs, normal fibroblasts are directly or indirectly activated into CAFs, and their metabolic characteristics are changed; thus, CAFs can more effectively promote tumor progression. Moreover, via ncRNAs, activated CAFs can affect the gene expression and secretory characteristics of cells, alter the TME and enhance malignant biological processes in tumor cells to contribute to tumor promotion. Previously, ncRNA dysregulation was considered the main mechanism by which ncRNAs participate in the crosstalk between CAFs and tumor cells. Recently, however, exosomes containing ncRNAs have been identified as another vital mode of interaction between these two types of cells, with a more direct and clear function. Gaining an in-depth understanding of ncRNAs in CAFs and the complex regulatory network connecting CAFs with tumor cells might help us to establish more effective and safer approaches for cancer therapies targeting ncRNAs and CAFs and offer new hope for cancer patients.

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