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1.
Mol Cancer ; 21(1): 32, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35090469

RESUMO

N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic in recent years. M6A plays multifunctional roles in normal and abnormal biological processes, and its role may vary greatly depending on the position of the m6A motif. Programmed cell death (PCD) includes apoptosis, autophagy, pyroptosis, necroptosis and ferroptosis, most of which involve the breakdown of the plasma membrane. Based on the implications of m6A methylation on PCD, the regulators and functional roles of m6A methylation were comprehensively studied and reported. In this review, we focus on the high-complexity links between m6A and different types of PCD pathways, which are then closely associated with the initiation, progression and resistance of cancer. Herein, clarifying the relationship between m6A and PCD is of great significance to provide novel strategies for cancer treatment, and has a great potential prospect of clinical application.


Assuntos
Adenosina , Neoplasias , Adenosina/análogos & derivados , Adenosina/metabolismo , Apoptose/genética , Humanos , Metilação , Neoplasias/genética , Neoplasias/metabolismo
2.
Clin Transl Med ; 12(5): e778, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35522946

RESUMO

BACKGROUND: Solute carrier family 7 member 11 (SLC7A11) is overexpressed in multiple human tumours and functions as a transporter importing cystine for glutathione biosynthesis. It promotes tumour development in part by suppressing ferroptosis, a newly identified form of cell death that plays a pivotal role in the suppression of tumorigenesis. However, the role and underlying mechanisms of SLC7A11-mediated ferroptosis in hepatoblastoma (HB) remain largely unknown. METHODS: Reverse transcription quantitative real-time PCR (RT-qPCR) and western blotting were used to measure SLC7A11 levels. Cell proliferation, colony formation, lipid reactive oxygen species (ROS), MDA concentration, 4-HNE, GSH/GSSG ratio and cell death assays as well as subcutaneous xenograft experiments were used to elucidate the effects of SLC7A11 in HB cell proliferation and ferroptosis. Furthermore, MeRIP-qPCR, dual luciferase reporter, RNA pulldown, RNA immunoprecipitation (RIP) and RACE-PAT assays were performed to elucidate the underlying mechanism through which SLC7A11 was regulated by the m6A modification in HB. RESULTS: SLC7A11 expression was highly upregulated in HB. SLC7A11 upregulation promoted HB cell proliferation in vitro and in vivo, inhibiting HB cell ferroptosis. Mechanistically, SLC7A11 mRNA exhibited abnormal METTL3-mediated m6A modification, which enhanced its stability and expression. IGF2 mRNA-binding protein 1 (IGF2BP1) was identified as the m6A reader of SLC7A11, enhancing SLC7A11 mRNA stability and expression by inhibiting SLC7A11 mRNA deadenylation in an m6A-dependent manner. Moreover, IGF2BP1 was found to block BTG2/CCR4-NOT complex recruitment via competitively binding to PABPC1, thereby suppressing SLC7A11 mRNA deadenylation. CONCLUSIONS: Our findings demonstrated that the METTL3-mediated SLC7A11 m6A modification enhances HB ferroptosis resistance. The METTL3/IGF2BP1/m6A modification promotes SLC7A11 mRNA stability and upregulates its expression by inhibiting the deadenylation process. Our study highlights a critical role of the m6A modification in SLC7A11-mediated ferroptosis, providing a potential strategy for HB therapy through blockade of the m6A-SLC7A11 axis.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Ferroptose , Hepatoblastoma , Proteínas Imediatamente Precoces , Neoplasias Hepáticas , Adenosina/análogos & derivados , Adenosina/farmacologia , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Animais , Ferroptose/genética , Hepatoblastoma/genética , Humanos , Proteínas Imediatamente Precoces/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metiltransferases/genética , Metiltransferases/metabolismo , RNA Mensageiro/genética , Proteínas Supressoras de Tumor/metabolismo
3.
Nat Commun ; 13(1): 2540, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534484

RESUMO

Epitranscriptomic features, such as single-base RNA editing, are sources of transcript diversity in cancer, but little is understood in terms of their spatial context in the tumour microenvironment. Here, we introduce spatial-histopathological examination-linked epitranscriptomics converged to transcriptomics with sequencing (Select-seq), which isolates regions of interest from immunofluorescence-stained tissue and obtains transcriptomic and epitranscriptomic data. With Select-seq, we analyse the cancer stem cell-like microniches in relation to the tumour microenvironment of triple-negative breast cancer patients. We identify alternative splice variants, perform complementarity-determining region analysis of infiltrating T cells and B cells, and assess adenosine-to-inosine base editing in tumour tissue sections. Especially, in triple-negative breast cancer microniches, adenosine-to-inosine editome specific to different microniche groups is identified.


Assuntos
Adenosina Desaminase , Neoplasias de Mama Triplo Negativas , Adenosina/genética , Adenosina Desaminase/genética , Humanos , Inosina/genética , Células-Tronco Neoplásicas , Microambiente Tumoral/genética
4.
Bioengineered ; 13(5): 11541-11550, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35502827

RESUMO

N6-methyladenosine (m6A) modification acts as the most prevalent internal modification in eukaryotic mRNA. Emerging evidence shows the critical biological roles of m6A key enzymes in human cancers. However, the roles of m6A binding protein IGF2BP2 in gastric cancer (GC) progression are still unclear. In this study, we confirmed that IGF2BP2 was highly expressed in GC cell lines and tumor tissues. Knocking down of IGF2BP2 suppressed cell proliferation and migration, and repressed xenograft tumor growth in vivo, while IGF2BP2 overexpression promoted the proliferation and migration. Mechanistically, we identified that IGF2BP2 regulated GC the proliferation/migration through recognizing the m6A modification sites of SIRT1 mRNA. In general, our findings demonstrated a novel regulatory mechanism that IGF2BP2/SIRT1 axis modulated GC progression in an m6A-dependent manner, suggesting that m6A may be a therapeutic target for GC.


Assuntos
Neoplasias Gástricas , Adenosina/análogos & derivados , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Mensageiro , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Neoplasias Gástricas/patologia
5.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(1): 109-115, 2022 Jan 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-35545370

RESUMO

N6-methyladenosine (m6A) methylation modification is one of the most common epigenetic modifications for eukaryotic mRNA. Under the catalytic regulation of relevant enzymes, m6A participates in the body's pathophysiological processes via mediating RNA transcription, splicing, translation, and decay. In the past, we mainly focused on the regulation of m6A in tumors such as hematological tumors, cervical cancer, breast cancer. In recent years, it has been found that m6A is enriched in mRNAs of neurogenesis, cell cycle, and neuron differentiation. Its regulation in the nervous system is gradually being recognized. When the level of m6A modification and the expression levels of relevant enzyme proteins are changed, it will cause neurological dysfunction and participate in the occurrence and conversion of neurological diseases. Recent studies have found that the m6A modification and its associated enzymes were involved in major depressive disorder, Parkinson's disease, Alzheimer's disease, Fragile X syndrome, amyotrophic lateral sclerosis, and traumatic brain injury, and they also play a key role in the development of neurological diseases and many other neurological diseases. This paper mainly reviewed the recent progress of m6A modification-related enzymes, focusing on the impact of m6A modification and related enzyme-mediated regulation of gene expression on the central nervous system diseases, so as to provide potential targets for the prevention of neurological diseases.


Assuntos
Transtorno Depressivo Maior , Adenosina/metabolismo , Epigênese Genética , Humanos , Metilação , RNA Mensageiro/metabolismo
6.
Front Immunol ; 13: 826943, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35529844

RESUMO

Heart transplantation remains the optimal treatment option for patients with end-stage heart disease. Growing evidence demonstrates that purinergic signals mediated by purine nucleotides and nucleosides play vital roles in heart transplantation, especially in the era of ischemia-reperfusion injury (IRI) and allograft rejection. Purinergic signaling consists of extracellular nucleotides and nucleosides, ecto-enzymes, and cell surface receptors; it participates in the regulation of many physiological and pathological processes. During transplantation, excess adenosine triphosphate (ATP) levels are released from damaged cells, and driver detrimental inflammatory responses largely via purinergic P2 receptors. Ecto-nucleosidases sequentially dephosphorylate extracellular ATP to ADP, AMP, and finally adenosine. Adenosine exerts a cardioprotective effect by its anti-inflammatory, antiplatelet, and vasodilation properties. This review focused on the role of purinergic signaling in IRI and rejection after heart transplantation, as well as the clinical applications and prospects of purinergic signaling.


Assuntos
Transplante de Coração , Nucleosídeos , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Humanos , Nucleotídeos/metabolismo
7.
BMC Med Genomics ; 15(1): 103, 2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513840

RESUMO

BACKGROUND: This is the first study to explore the potential functions and expression patterns of RNA N6-methyladenosine (m6A) and potential related genes in preeclampsia. METHODS: We identified two m6A modification patterns through unsupervised cluster analysis and validated them by principal component analysis. We quantified the relative abundance of specific infiltrating immunocytes using single-sample gene set enrichment analysis (ssGSEA) and the Wilcoxon test. To screen hub genes related to m6A regulators, we performed weighted gene coexpression network analysis. Functional enrichment analysis was conducted for differential signalling pathways and cellular processes. Preeclampsia patients were grouped by consensus clustering based on differentially expressed hub genes and the relationship between different gene-mediated classifications and clinical features. RESULTS: Two m6A clusters in preeclampsia, cluster A and cluster B, were determined based on the expression of 17 m6A modification regulators; ssGSEA revealed seven significantly different immune cell subtypes between the two clusters. A total of 1393 DEGs and nine potential m6A-modified hub genes were screened. We divided the patients into two groups based on the expression of these nine genes. We found that almost all the patients in m6A cluster A were classified into hub gene cluster 1 and that a lower gestational age may be associated with more m6A-associated events. CONCLUSIONS: This study revealed that hub gene-mediated classification is consistent with m6A modification clusters for predicting the clinical characteristics of patients with preeclampsia. Our results provide new insights into the molecular mechanisms of preeclampsia.


Assuntos
Pré-Eclâmpsia , Adenosina/genética , Adenosina/metabolismo , Feminino , Redes Reguladoras de Genes , Humanos , Pré-Eclâmpsia/genética , Gravidez , Prognóstico , RNA/metabolismo
8.
Biomed Res Int ; 2022: 2677312, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35528183

RESUMO

FTO (fat mass and obesity associated) is a recently discovered gene related to obesity and expressed in various tissues of the human body, especially with high expression in the brain. Earlier studies have found that FTO is involved in several biological processes, including brain development and function. In particular, recent studies have found that FTO is a demethylase of N6-methyladenosine (m6A) and it can affect neurological function through the m6A modification of mRNA. At present, a number of studies have shown that FTO is associated with many neuropsychiatric disorders. This paper reviews the discovery, structure, function, and tissue expression of FTO followed by discussing the relationship between FTO and neuropsychiatric diseases. In addition, the potential roles of FTO gene in drug addiction, major depression (MDD), and schizophrenia (SCZ) through regulating m6A modification of dopamine related genes were also highlighted.


Assuntos
Adenosina , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Encefalopatias , Transtornos Mentais , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Encefalopatias/genética , Humanos , Transtornos Mentais/genética , Obesidade/genética , RNA Mensageiro/genética
9.
Cancer Res ; 82(9): 1789-1802, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35502544

RESUMO

The RNA N6-methyladenosine (m6A) writer methyltransferase-like 3 (METTL3) is upregulated in many types of cancer and promotes cancer progression by increasing expression of several oncogenes. Therefore, a better understanding of the mechanisms regulating METTL3 expression and the key targets of METTL3 in cancer cells could provide new therapeutic targets. In this study, we found that activated JNK signaling is associated with increased METTL3 expression in bladder cancer. Knockdown of JNK1 or administration of a JNK inhibitor impaired the binding of c-Jun with the METTL3 promoter, thereby decreasing the expression of METTL3 and global RNA m6A levels. Moreover, RNA m6A sequencing indicated enrichment of m6A in the 3'-UTR of immune checkpoint PD-L1 mRNA, which could be recognized by the m6A reader IGF2BP1 to mediate RNA stability and expression levels of PD-L1. Inhibition of JNK signaling suppressed m6A abundance in PD-L1 mRNA, leading to decreased PD-L1 expression. Functionally, METTL3 was essential for bladder cancer cells to resist the cytotoxicity of CD8+ T cells by regulating PD-L1 expression. Additionally, JNK signaling contributed to tumor immune escape in a METTL3-dependent manner both in vitro and in vivo. These data reveal the JNK/METTL3 axis as a mechanism of aberrant m6A modification and immune regulation in bladder cancer. SIGNIFICANCE: The identification of a novel m6A-dependent mechanism underlying immune system evasion by bladder cancer cells reveals JNK signaling as a potential target for bladder cancer immunotherapy.


Assuntos
Neoplasias da Bexiga Urinária , Adenosina/metabolismo , Antígeno B7-H1/genética , Feminino , Humanos , Masculino , Glicoproteínas de Membrana , Metiltransferases/genética , Metiltransferases/metabolismo , Proteína Quinase 8 Ativada por Mitógeno , Proteínas do Tecido Nervoso , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias da Bexiga Urinária/patologia
10.
Purinergic Signal ; 18(2): 205-209, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35501535

RESUMO

Quorum sensing indicates a communication process between bacteria based on a coordinate variation in gene expression aimed at coordinating a collective comportment related to the bacterial population density. Increasing pieces of evidence pointed out that a quorum-sensing system can be a regulatory program also used in the immune field to organize the density of the various immune cell populations and to calibrate their responses. In particular, such equilibrium is achieved by the ability of immune cells to perceive the density of their own populations or those of other cells in their environment, through the release of several mediators able to finely shape the cell density via coordinated changes in gene expression and protein signaling. In this regard, adenosine displays the typical characteristics of a mediator involved in the regulation of quorum sensing, thus suggesting a putative role of this nucleoside in shaping the balance between diverse immune cell populations.


Assuntos
Adenosina , Percepção de Quorum , Transdução de Sinais
11.
BMC Genomics ; 23(1): 358, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35538402

RESUMO

BACKGROUND AND AIM: Yak estrus is a seasonal phenomenon, probably involving epigenetic regulation of synthesis and secretion of sex hormones as well as growth and development of follicles. N6-methyladenosine (m6A) is the most common internal modification of the eukaryotic mRNA. However, there are no detailed reports on the m6A transcriptome map of yak ovary. Therefore, this study aimed to collected the yak ovarian tissues at three different states of anestrus (YO-A), estrus (YO-F), and pregnancy (YO-P), and obtained the full transcriptome m6A map in yak by MeRIP-seq. RESULTS: The HE staining revealed that the number of growing follicles and mature follicles in the ovary during the estrus period was relatively higher than those in the anestrus period and the pregnancy period. The RT-qPCR showed that the expression of METTL3, METTL14, FTO, YTHDC1 were significantly different across different periods in the ovaries, which suggests that m6A may play a regulatory role in ovarian activity. Next, we identified 20,174, 19,747 and 13,523 m6A peaks in the three ovarian samples of YO-A, YO-F and YO-P using the methylated RNA immunoprecipitation sequencing (MeRIP-seq). The m6A peaks are highly enriched in the coding sequence (CDS) region and 3'untranslated region (3'UTR) as well as the conserved sequence of "RRACH." The GO, KEGG and GSEA analysis revealed the involvement of m6A in many physiological activities of the yak's ovary during reproductive cycle. The association analysis found that some genes such as BNC1, HOMER1, BMP15, BMP6, GPX3, and WNT11 were related to ovarian functions. CONCLUSIONS: The comparison of the distribution patterns of methylation peaks in the ovarian tissues across different periods further explored the m6A markers related to the regulation of ovarian ovulation and follicular development in the yak ovary. This comprehensive map provides a solid foundation for revealing the potential function of the mRNA m6A modification in the yak ovary.


Assuntos
Ovário , Transcriptoma , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Animais , Bovinos , Epigênese Genética , Feminino , Ovário/metabolismo , Gravidez , RNA Mensageiro/genética
12.
Mol Cancer ; 21(1): 111, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538475

RESUMO

BACKGROUND: Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear. METHODS: RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis. RESULTS: We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment. CONCLUSIONS: Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients.


Assuntos
Adenosina , Carcinoma de Células Renais , Neoplasias Renais , Metiltransferases , Sunitinibe , Fator 1 Associado a Receptor de TNF , Adenosina/análogos & derivados , Inibidores da Angiogênese/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Metiltransferases/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Sunitinibe/farmacologia , Fator 1 Associado a Receptor de TNF/genética , Fator 1 Associado a Receptor de TNF/metabolismo
13.
Zhongguo Fei Ai Za Zhi ; 25(5): 311-322, 2022 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-35599007

RESUMO

BACKGROUND: m6A RNA methylation modification plays an important role in the occurrence and progression of lung cancer and regulates tumor immunity. Current studies mostly focus on the differential expression of some specific m6A effectors and infiltrating immune cell. m6A methylation modification is the result of mutual adjustment and balance between effectors, and changes in the expression of one or two effectors are far from enough to reflect the panorama of m6A methylation. The role of m6A in the immune microenvironment of lung adenocarcinoma (LUAD) is still poorly understood. The aim of this study is to investigate the effect of different m6A modification patterns in immune microenvironment of LUAD. METHODS: LUAD data was obtained from The Cancer Genome Atlas (TCGA), University of California Santa Cruz Xena (UCSC Xena) and Gene Expression Omnibus (GEO) databases. Gene mutation, differential expression and survival analysis were performed for 24 m6A effectors. The m6A modification pattern was constructed by unsupervised clustering method, and the m6A clusters survival analysis, gene set variation analysis, immune score and immune cell infiltration analysis were performed. The association between LRPPRC protein expression levels and infiltration of CD8+ cytotoxic T lymphocytes and CD68+ macrophages in the tumor microenvironment was validated by immunohistochemistry in LUAD tissue microarray with 68 cases. RESULTS: The mutations of m6A effector were found in 150 of 567 LUAD cases with a frequency of 26.46%. 6 readers and 3 writers were significantly up regulated in LUAD tissues compared with normal tissues. IGF2BP1 and HNRNPC are the independent risk factors for prognosis of LUAD. Abundant cross-talks among writers, erasers and readers were demonstrated. Three m6A modification patterns with different immune cell infiltration characteristics and clinical prognosis were established. Among m6A effectors, LRPPRC was found to be inversely associated with the infiltration of CD8+ cytotoxic T lymphocytes and CD68+ macrophages, and was validated in 68 LUAD tissues. CONCLUSIONS: m6A modification patterns play non-negligible roles in regulating the immune microenvironment. LRPPRC has potential to be a new biomarker for checkpoint inhibitor immunotherapy.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/patologia , Adenosina/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Metilação , Microambiente Tumoral/genética
14.
Purinergic Signal ; 18(2): 193-198, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35522386

RESUMO

Historically, mainly by the work of Robert Berne, extracellular adenosine was the first purine compound recognized as an important signaling molecule linking energy metabolism to function by acting on membrane bound receptors. Geoffrey Burnstock by his vision and endurance pioneered the idea that cells release ATP that also acts as an extracellular signaling molecule under many physiological and pathophysiological circumstances. Only later, it was appreciated that extracellular ATP and adenosine are metabolically linked by the activity of several ectoenzymes which critically determine the concentrations of these purines at their respective receptors. In this brief review, I will report some personal recollections on Geoffrey Burnstock and his impressive personality. In addition, I will give a brief overview on our present knowledge of extracellular purine metabolism and its control and will address some still open issues.


Assuntos
Adenosina , Receptores Purinérgicos , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Metabolismo Energético , Receptores Purinérgicos/metabolismo , Transdução de Sinais/fisiologia
15.
J Transl Med ; 20(1): 197, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35509079

RESUMO

BACKGROUND: N6-methyladenosine (m6A) RNA methylation plays a critical role in key genetic events for various cancers; yet, how m6A functions within the tumor microenvironment (TME) remains to be elucidated. METHODS: A total of 65,362 single cells from single-cell RNA-seq data derived from 33 CRC tumor samples were analyzed by nonnegative matrix factorization (NMF) for 23 m6A RNA methylation regulators. CRC and Immunotherapy cohorts from public repository were used to determine the prognosis and immune response of TME clusters. RESULTS: The fibroblasts, macrophages, T and B cells were respectively grouped into 4 to 5 subclusters and then classified according to various biological processes and different marker genes. Furthermore, it revealed that the m6A RNA methylation regulators might be significantly related to the clinical and biological features of CRC, as well as the pseudotime trajectories of main TME cell types. Bulk-seq analysis suggested that these m6A-mediated TME cell subclusters had significant prognostic value for CRC patients and distinguished immune response for patients who underwent ICB therapy, especially for the CAFs and macrophages. Notably, CellChat analysis revealed that RNA m6A methylation-associated cell subtypes of TME cells manifested diverse and extensive interaction with tumor epithelial cells. Further analysis showed that ligand-receptor pairs, including MIF - (CD74 + CXCR4), MIF - (CD74 + CD44), MDK-NCL and LGALS9 - CD45, etc. mediated the communication between m6A associated subtypes of TME cells and tumor epithelial cells. CONCLUSIONS: Taken together, our study firstly revealed the m6A methylation mediated intercellular communication of the tumor microenvironment in the regulation of tumor growth and antitumor immunomodulatory processes.


Assuntos
Neoplasias Colorretais , Microambiente Tumoral , Adenosina/análogos & derivados , Biomarcadores Tumorais/genética , Comunicação Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Humanos , Imunoterapia , RNA/metabolismo
17.
Front Endocrinol (Lausanne) ; 13: 853857, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35370940

RESUMO

Objective: The objective of this study was to reveal the potential crosstalk between immune infiltration and N6- methyladenosine (m6A) modification in the placentas of patients with gestational diabetes mellitus (GDM), and to construct a model for the diagnosis of GDM. Methods: We analyzed imbalanced immune infiltration and differentially expressed m6A-related genes (DMRGs) in the placentas of patients with GDM, based on the GSE70493 dataset. An immune-related DMRG signature, with significant classifying power and diagnostic value, was identified using a least absolute shrinkage and selection operator (LASSO) regression. Based on the selected DMRGs, we developed and validated a nomogram model using GSE70493 and GSE92772 as the training and validation sets, respectively. Results: Infiltration of monocytes was higher in GDM placentas than in control samples, while the infiltration of macrophages (M1 and M2) in GDM placentas was lower than in controls. A total of 14 DMRGs were strongly associated with monocyte infiltration, seven of which were significant in distinguishing patients with GDM from normal controls. These genes were CD81, CFH, FABP5, GBP1, GNG11, IL1RL1, and SLAMF6. The calibration curve, decision curve, clinical impact curve, and receiver operating characteristic curve showed that the nomogram recognized GDM with high accuracy in both the training and validation sets. Conclusions: Our results provide clues that crosstalk between m6A modification and immune infiltration may have implications in terms of novel biomarkers and therapeutic targets for GDM.


Assuntos
Diabetes Gestacional , Adenosina/análogos & derivados , Biomarcadores , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/genética , Proteínas de Ligação a Ácido Graxo , Feminino , Humanos , Monócitos , Gravidez , Curva ROC
18.
Cell Death Dis ; 13(4): 294, 2022 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-35365616

RESUMO

Adenosine (A) to inosine (I) RNA editing catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes is a post-transcriptional modification that emerged as a key player in tumorigenesis and cancer progression. Antizyme inhibitor 1 (AZIN1) is one of the most frequent A-to-I RNA alterations in many human cancers. RNA-edited AZIN1 is known to confer a gain-of-function phenotype associated with aggressive tumors. However, the functional impact of RNA-edited AZIN1 in cancer angiogenesis remains unexplored. We showed here that RNA-edited AZIN1 promoted tumor angiogenesis through the upregulation of IL-8 via in vitro and in vivo experiments. And we subsequently demonstrated that delaying c-Myc degradation by OAZ2-mediated ubiquitin-independent proteasome pathway contributed to increase mRNA level and the secretion of angiogenic factor IL-8. Our study suggests an important contribution of RNA-edited AZIN1 to the tumor vascular microenvironment and highlights its translational potential. Thus, we revealed a potential approach to explore small-molecule antagonists such as reparixin attenuating IL-8 signaling for treatment of human cancer patients detected with hyper-editing.


Assuntos
Neoplasias Colorretais , Interleucina-8 , Adenosina , Adenosina Desaminase/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , RNA , Microambiente Tumoral
19.
Front Immunol ; 13: 866097, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35479074

RESUMO

Adenosine is a purine nucleoside that, via activation of distinct G protein-coupled receptors, modulates inflammation and immune responses. Under pathological conditions and in response to inflammatory stimuli, extracellular ATP is released from damaged cells and is metabolized to extracellular adenosine. However, studies over the past 30 years provide strong evidence for another source of extracellular adenosine, namely the "cAMP-adenosine pathway." The cAMP-adenosine pathway is a biochemical mechanism mediated by ATP-binding cassette transporters that facilitate cAMP efflux and by specific ectoenzymes that convert cAMP to AMP (ecto-PDEs) and AMP to adenosine (ecto-nucleotidases such as CD73). Importantly, the cAMP-adenosine pathway is operative in many cell types, including those of the airways. In airways, ß2-adrenoceptor agonists, which are used as bronchodilators for treatment of asthma and chronic respiratory diseases, stimulate cAMP efflux and thus trigger the extracellular cAMP-adenosine pathway leading to increased concentrations of extracellular adenosine in airways. In the airways, extracellular adenosine exerts pro-inflammatory effects and induces bronchoconstriction in patients with asthma and chronic obstructive pulmonary diseases. These considerations lead to the hypothesis that the cAMP-adenosine pathway attenuates the efficacy of ß2-adrenoceptor agonists. Indeed, our recent findings support this view. In this mini-review, we will highlight the potential role of the extracellular cAMP-adenosine pathway in chronic respiratory inflammatory disorders, and we will explore how extracellular cAMP could interfere with the regulatory effects of intracellular cAMP on airway smooth muscle and innate immune cell function. Finally, we will discuss therapeutic possibilities targeting the extracellular cAMP-adenosine pathway for treatment of these respiratory diseases.


Assuntos
Adenosina , Asma , Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/uso terapêutico , Asma/tratamento farmacológico , Humanos , Receptores Adrenérgicos , Transdução de Sinais/fisiologia
20.
Comput Math Methods Med ; 2022: 2172412, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35479188

RESUMO

Ulinastatin, a common adjuvant drug in the clinical treatment of acute circulatory failure, has a good effect on various inflammatory diseases. In this study, we aim to explore the clinical efficacy of ulinastatin combined with meglumine adenosine cyclophosphate in patients with acute myocardial infarction (AMI) and its effect on cardiac function and endothelial function of patients. 100 AMI patients treated in our hospital (February 2020-October 2020) were randomly chosen and divided into group J and group Q, with 50 cases in each group. Group Q was treated with meglumine adenosine cyclophosphate only, while group J was treated with ulinastatin combined with meglumine adenosine cyclophosphate to compare the treatment efficiency, cardiac structure indexes, cardiac systolic function, blood lipid levels, vascular endothelial function, QLI (quality of life) scores, BI indexes, and FMA (motor function) scores between the two groups. The treatment efficiency, QLI score, BI index, and FMA score in group J were notably higher compared with group Q (P < 0.05). The cardiac structure indexes, cardiac systolic function, blood lipid level, and vascular endothelial function in group J were notably better compared with group Q (P < 0.05). Ulinastatin combined with meglumine adenosine cyclophosphate can obviously enhance the therapeutic effect of AMI patients and improve the endothelial function and cardiac function of patients, which is very promising in this medical area.


Assuntos
Adenosina , Infarto do Miocárdio , Adenosina/uso terapêutico , Glicoproteínas , Humanos , Meglumina/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Qualidade de Vida , Resultado do Tratamento
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