RESUMEN

Previous studies have demonstrated that genetic alterations governing epigenetic processes frequently drive tumor development and that modifications in RNA may contribute to these alterations. In the 1970s, researchers discovered that N6-methyladenosine (m6A) is the most prevalent form of RNA modification in advanced eukaryotic messenger RNA (mRNA) and noncoding RNA (ncRNA). This modification is involved in nearly all stages of the RNA life cycle. M6A modification is regulated by enzymes known as m6A methyltransferases (writers) and demethylases (erasers). Numerous studies have indicated that m6A modification can impact cancer progression by regulating cancer-related biological functions. Tumor angiogenesis, an important and unregulated process, plays a pivotal role in tumor initiation, growth, and metastasis. The interaction between m6A and ncRNAs is widely recognized as a significant factor in proliferation and angiogenesis. Therefore, this article provides a comprehensive review of the regulatory mechanisms underlying m6A RNA modifications and ncRNAs in tumor angiogenesis, as well as the latest advancements in molecular targeted therapy. The aim of this study is to offer novel insights for clinical tumor therapy.

Asunto(s)

Adenosina , Neoplasias , Neovascularización Patológica , Adenosina/análogos & derivados , Adenosina/metabolismo , Humanos , Neovascularización Patológica/genética , Neoplasias/genética , Neoplasias/patología , Neoplasias/irrigación sanguínea , Animales , Regulación Neoplásica de la Expresión Génica , ARN no Traducido/genética , Metiltransferasas/metabolismo , Metiltransferasas/genética , Angiogénesis

RESUMEN

N6-methyladensine (m6A) has been identified as the best-characterized and the most abundant mRNA modification in eukaryotes. It can be dynamically regulated, removed, and recognized by its specific cellular components (respectively called "writers," "erasers," "readers") and have become a hot research field in a variety of biological processes and diseases. Currently, the underlying molecular mechanisms of m6A epigenetic modification in diabetes mellitus (DM) and diabetic microvascular complications have not been extensively clarified. In this review, we focus on the effects and possible mechanisms of m6A as possible potential biomarkers and therapeutic targets in the treatment of DM and diabetic microvascular complications.

Asunto(s)

Angiopatías Diabéticas , Epigénesis Genética , Humanos , Angiopatías Diabéticas/genética , Angiopatías Diabéticas/metabolismo , Animales , Metilación , Adenina/análogos & derivados , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Metilación de ARN

RESUMEN

N6-methyladenosine (m6A) RNA methylation is a prevalent RNA modification that significantly impacts RNA metabolism and cancer development. Maintaining the global m6A levels in cancer cells relies on RNA accessibility to methyltransferases and the availability of the methyl donor S-adenosylmethionine (SAM). Here, we reveal that death associated protein 3 (DAP3) plays a crucial role in preserving m6A levels through two distinct mechanisms. First, although DAP3 is not a component of the m6A writer complex, it directly binds to m6A target regions, thereby facilitating METTL3 binding. Second, DAP3 promotes MAT2A's last intron splicing, increasing MAT2A protein, cellular SAM, and m6A levels. Silencing DAP3 hinders tumorigenesis, which can be rescued by MAT2A overexpression. This evidence suggests DAP3's role in tumorigenesis, partly through m6A regulation. Our findings unveil DAP3's complex role as an RNA-binding protein and tumor promoter, impacting RNA processing, splicing, and m6A modification in cancer transcriptomes.

Asunto(s)

Adenosina , Metionina Adenosiltransferasa , Metiltransferasas , Neoplasias , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Metiltransferasas/metabolismo , Metiltransferasas/genética , Metionina Adenosiltransferasa/metabolismo , Metionina Adenosiltransferasa/genética , Neoplasias/genética , Neoplasias/metabolismo , Metilación , Línea Celular Tumoral , S-Adenosilmetionina/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Empalme del ARN/genética , Animales , Ratones , ARN/metabolismo , ARN/genética , Procesamiento Postranscripcional del ARN , Metilación de ARN

RESUMEN

Skeletal muscle development is a complex, regulated physiological process that involves myoblast proliferation and differentiation and the fusion of myotubes. In this study, phenotypic differences in the breast and leg muscles of 180-day-old Jingyuan chickens were investigated. Differentially methylated genes (DMG) that regulate muscle development were identified through differential expression analysis and weighted gene co-expression network analysis. Moreover, myoblasts were used as test material and treated with cycloleucine to investigate the effect of N6-methyladenosine (m6A) modification on their proliferation and differentiation. The results revealed that the myofiber diameter and cross-sectional area in the breast muscle of Jingyuan chickens were significantly smaller than those in the leg muscle, while myofiber density in the breast muscle was significantly higher. A total of 484 DMG were identified in both muscle types. Module gene association analysis with DMGs revealed multiple DMG associated with muscle development. In vitro cell model analysis revealed that cycloleucine treatment significantly downregulated the m6A modification level of myoblasts and inhibited their proliferation and differentiation. Additionally, stage-specific differences in LDHA, LDHB, and GAPDH expressions were observed during myoblast differentiation. Cycloleucine treatment significantly inhibited LDHA, LDHB, and GAPDH expression. These findings indicate that m6A methylation modifications play significant regulatory roles in muscle development, with LDHA, LDHB, and GAPDH being potential candidate genes for regulating muscle development. This study provides an essential theoretical basis for further study on the functional mechanisms of m6A modifications involved in muscle development.

RESUMEN

N6-methyladenosine (m6A) is the most common and prevalent internal mRNA modification in eukaryotes. m6A modification is a dynamic and reversible process regulated by methyltransferases, demethylases, and m6A binding proteins. Skin cancers, including melanoma and nonmelanoma skin cancers (NMSCs), are among the most commonly diagnosed cancers worldwide. m6A methylation is involved in the regulation of RNA splicing, translation, degradation, stability, translocation, export, and folding. Aberrant m6A modification participates in the pathophysiological processes of skin cancers and is associated with tumor cell proliferation, invasion, migration, and metastasis during cancer progression. In this review, we provide a comprehensive summary of the biological functions of m6A and the most up-to-date evidence related to m6A RNA modification in skin cancer. We also emphasize the potential clinical applications in the diagnosis and treatment of skin cancers.

RESUMEN

Septic cardiomyopathy is a secondary myocardial injury caused by sepsis. N6-methyl-adenosine (m6A) modification is involved in the pathological progression of septic cardiomyopathy; however, the pathological mechanism remains unclear. In this study, we identified the overall m6A modification pattern in septic myocardial injury and determined its potential interactions with differentially expressed genes (DEGs). A sepsis mouse model exhibiting septic symptoms and myocardial tissue damage was induced by lipopolysaccharide (LPS). LPS-induced septic myocardial tissues and control myocardial tissues were subjected to methylated RNA immunoprecipitation sequencing and RNA sequencing to screen for differentially expressed m6A peaks and DEGs. We identified 859 significantly m6A-modified genes in septic myocardial tissues, including 432 upregulated and 427 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to explore the biological importance of differentially expressed m6A methylated genes and DEGs. Differentially expressed m6A methylated genes were enriched in immune- and inflammation-related pathways. Conjoint analysis revealed co-expression of differentially expressed m6A genes and DEGs, including genes that were upregulated or downregulated and those showing opposite trends. High expression of m6A-related genes (WTAP and IGF2BP2), interleukin-17, and interleukin-17 pathway-related genes (MAPK11 and TRAF3IP2) was verified using reverse transcription-quantitative PCR. We confirmed the presence of m6A modification of the transcriptome and m6A-mediated gene expression in septic myocardial tissues.

Asunto(s)

Adenosina , Miocardio , Sepsis , Animales , Ratones , Sepsis/genética , Sepsis/metabolismo , Miocardio/metabolismo , Miocardio/patología , Metilación , Adenosina/metabolismo , Adenosina/análogos & derivados , Masculino , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Transcriptoma , Ratones Endogámicos C57BL , Lipopolisacáridos

RESUMEN

Medulloblastoma, the most common malignant pediatric brain tumor, is classified into four main molecular subgroups, but group 3 and group 4 tumors are difficult to subclassify and have a poor prognosis. Rapid point-of-care diagnostic and prognostic assays are needed to improve medulloblastoma risk stratification and management. N6-methyladenosine (m6A) is a common RNA modification and long non-coding RNAs (lncRNAs) play a central role in tumor progression, but their impact on gene expression and associated clinical outcomes in medulloblastoma are unknown. Here we analyzed 469 medulloblastoma tumor transcriptomes to identify lncRNAs co-expressed with m6A regulators. Using LASSO-Cox analysis, we identified a five-gene m6A-associated lncRNA signature (M6LSig) significantly associated with overall survival, which was combined in a prognostic clinical nomogram. Using expression of the 67 m6A-associated lncRNAs, a subgroup classification model was generated using the XGBoost machine learning algorithm, which had a classification accuracy > 90%, including for group 3 and 4 samples. All M6LSig genes were significantly correlated with at least one immune cell type abundance in the tumor microenvironment, and the risk score was positively correlated with CD4+ naïve T cell abundance and negatively correlated with follicular helper T cells and eosinophils. Knockdown of key m6A writer genes METTL3 and METTL14 in a group 3 medulloblastoma cell line (D425-Med) decreased cell proliferation and upregulated many M6LSig genes identified in our in silico analysis, suggesting that the signature genes are functional in medulloblastoma. This study highlights a crucial role for m6A-dependent lncRNAs in medulloblastoma prognosis and immune responses and provides the foundation for practical clinical tools that can be rapidly deployed in clinical settings.

RESUMEN

BACKGROUND: Growth hormone-secreting pituitary neuroendocrine tumors can be pathologically classified into densely granulated (DGGH) and sparsely granulated types (SGGH). SGGH is more aggressive and associated with a poorer prognosis. While epigenetic regulation is vital in tumorigenesis and progression, the role of N6-methyladenosine (m6A) in aggressive behavior has yet to be elucidated. METHODS: We performed m6A-sequencing on tumor samples from 8 DGGH and 8 SGGH patients, complemented by a suite of assays including ELISA, immuno-histochemistry, -blotting and -fluorescence, qPCR, MeRIP, RIP, and RNA stability experiments, aiming to delineate the influence of m6A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies. RESULTS: We discovered a significant reduction of m6A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m6A demethylase, in SGGH subtype. Series of in vivo and in vitro experiments demonstrated that FTO inhibition in tumor cells robustly diminishes hypoxia resistance, attenuates growth hormone secretion, and augments responsiveness to octreotide. Mechanically, FTO-mediated m6A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m6A reader FMR1, leading to prohibited desmosome integrity and enhanced tumor hypoxia tolerance. Targeting the FTO-DSP-SSTR2 axis curtailed growth hormone secretion, therefor sensitizing tumors to octreotide therapy. CONCLUSION: Our study reveals the critical role of FTO in the aggressive growth hormone-secreting pituitary neuroendocrine tumors subtype and suggests FTO may represent a new therapeutic target for refractory/persistent SGGH.

Asunto(s)

Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Desmetilación , Tumores Neuroendocrinos , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Humanos , Animales , Ratones , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Femenino , Masculino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología

RESUMEN

BACKGROUND: N6-methyladenosine (m6A) and 5-methylcytosine (m5C) play a role in modifying long non-coding RNAs (lncRNAs) implicated in tumorigenesis and progression. This study was performed to evaluate prognostic value of m6A- and m5C-related lncRNAs and develop an efficient model for prognosis prediction in cervical cancer (CC). METHODS: Using gene expression data of TCGA set, we identified m6A- and m5C-related lncRNAs. Consensus Clustering Analysis was performed for samples subtyping based on survival-related lncRNAs, followed by analyzing tumor infiltrating immune cells (TIICs). Optimal signature lncRNAs were obtained using lasso Cox regression analysis for constructing a prognostic model and a nomogram to predict prognosis. RESULTS: We built a co-expression network of 23 m6A-related genes, 15 m5C-related genes, and 62 lncRNAs. Based on 9 m6A- and m5C-related lncRNAs significantly associated with overall survival (OS) time, two molecular subtypes were obtained, which had significantly different OS time and fractions of TIICs. A prognostic model based on six m6A- and m5C-related signature lncRNAs was constructed, which could dichotomize patients into two risk subgroups with significantly different OS time. Prognostic power of the model was successfully validated in an independent dataset. We subsequently constructed a nomogram which could accurately predict survival probabilities. Drug sensitivity analysis found preferred chemotherapeutic agents for high and low-risk patients, respectively. CONCLUSION: Our study reveals that m6A- and m5C-related lncRNAs are associated with prognosis and immune microenvironment of CC. The m6A- and m5C-related six-lncRNA signature may be a useful tool for survival stratification in CC and open new avenues for individualized therapies.

Asunto(s)

5-Metilcitosina , Adenosina , ARN Largo no Codificante , Neoplasias del Cuello Uterino , ARN Largo no Codificante/genética , Humanos , Adenosina/análogos & derivados , Adenosina/genética , Adenosina/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/diagnóstico , Femenino , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Pronóstico , Regulación Neoplásica de la Expresión Génica , Nomogramas , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica

RESUMEN

N6-methyladenosine (m6A) is known to be crucial in various biological processes, but its role in sepsis-induced circulatory and cardiac dysfunction is not well understood. Specifically, mitophagy, a specialized form of autophagy, is excessively activated during lipopolysaccharide (LPS)-induced myocardial injury. This study aimed to investigate the impact of LPS-induced endotoxemia on m6A-RNA methylation and its role in regulating mitophagy in sepsis-induced myocardial dysfunction. Our research demonstrated that FTO (fat mass and obesity-associated protein), an m6A demethylase, significantly affects abnormal m6A modification in the myocardium and cardiomyocytes following LPS treatment. In mice, cardiac dysfunction and cardiomyocyte apoptosis worsened after adeno-associated virus serotype 9 (AAV9)-mediated FTO knockdown. Further analyses to uncover the cellular mechanisms improving cardiac function showed that FTO reduced mitochondrial reactive oxygen species, restored both basal and maximal respiration, and preserved mitochondrial membrane potential. We revealed that FTO plays a critical role in activating mitophagy by targeting BNIP3. Additionally, the cardioprotective effects of AAV-FTO were significantly compromised by mdivi-1, a mitophagy inhibitor. Mechanistically, FTO interacted with BNIP3 transcripts and regulated their expression in an m6A-dependent manner. Following FTO silencing, BNIP3 transcripts with elevated m6A modification levels in their coding regions were bound by YTHDF2 (YT521-B homology m6A RNA-binding protein 2), leading to mRNA destabilization and decreased BNIP3 protein levels. These findings highlight the importance of FTO-dependent cardiac m6A methylation in regulating mitophagy and enhance our understanding of this critical interplay, which is essential for developing therapeutic strategies to protect cardiac mitochondrial function, alleviate cardiac dysfunction, and improve survival during sepsis.

RESUMEN

Vascular calcification and vascular ageing are "silent" diseases but are highly prevalent in patients with end stage renal failure and type 2 diabetes, as well as in the ageing population. Melatonin (MT) has been shown to induce cardiovascular protection effects. However, the role of MT on vascular calcification and ageing has not been well-identified. In this study, the aortic transcriptional landscape revealed clues for MT related cell-to-cell communication between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) in vascular calcification and vascular ageing. Furthermore, we elucidated that it was exosomes that participate in the information transportation from ECs to VSMCs. The exosomes secreted from melatonin-treated ECs (MT-ECs-Exos) inhibited calcification and senescence of VSMCs. Mechanistically, miR-302d-5p was highly enriched in MT-ECs-Exos, while depletion of miR-302d-5p blocked the ability of MT-ECs-Exos to suppress VSMC calcification and senescence. Notably, Wnt3 was a bona fide target of miR-302d-5p and modulated VSMC calcification and senescence. Furthermore, we found that maturation of endothelial derived exosomal miR-302d-5p was promoted by WTAP in an N6-methyladenosine (m6A)-dependent manner. Interestingly, MT alleviated vascular calcification and ageing in 5/6-nephrectomy (5/6 NTP) mice, a chronic kidney disease (CKD) induced vascular calcification and vascular ageing mouse model. MT-ECs-Exos was absorbed by VSMCs in vivo and effectively prevented vascular calcification and ageing in 5/6 NTP mice. ECs-derived miR-302d-5p mediated MT induced anti-calcification and anti-ageing effects in 5/6 NTP mice. Our study suggests that MT-ECs-Exos alleviate vascular calcification and ageing through the miR-302d-5p/Wnt3 signaling pathway, dependent on m6A methylation.

RESUMEN

As the most abundant modification in eukaryotic messenger RNA (mRNA) and long noncoding RNA (lncRA), N6-methyladenosine (m6A) has been shown to play essential roles in various significant biological processes and attracted growing attention in recent years. To investigate its functions and dynamics, there is a critical need to quantitatively determine the m6A modification fractions at a precise location. Here, we report a deoxyribozyme mediated CRISPR-Cas12a platform (termed "DCAS") that can directly quantify m6A fractions at single-base resolution. DCAS employs a deoxyribozyme (VMC10) to selectively cleave the unmodified adenine (A) in the RNA, allowing only m6A-modified RNA amplified by RT-PCR. Leveraging the CRISPR-Cas12a quantify the PCR amplification products, DCAS can directly determine the presence of m6A at target sites and its fractions. The combination of CRISPR-Cas12a with RT-PCR has greatly improved the sensitivity and accuracy, enabling the detection of m6A-modified RNA as low as 100 aM in 2 fM total target RNA. This robustly represents an improvement of 2-3 orders of magnitude of sensitivity and selectivity compared to traditional standard methods, such as SCARLET and primer extension methods. Therefore, this method can be successfully employed to accurately determine m6A fractions in real biological samples, even in low abundance RNA biomarkers.

RESUMEN

The occurrence of metastasis is a major factor contributing to poor prognosis in colorectal cancer. Different stages of the disease play a crucial role in distant metastasis. Furthermore, m6A has been demonstrated to play a significant role in regulating tumor metastasis. Therefore, we conducted an analysis of transcriptome data from high-stage and low-stage colorectal cancer patients in The Cancer Genome Atlas (TCGA) to identify genes associated with m6A-related regulation. We identified SYNPO2L as a core gene regulated by m6A, and it is correlated with adverse prognosis and metastasis in patients. Additionally, we demonstrated that the m6A writer gene Mettl16 can regulate the stability of SYNPO2L through interaction with YTHDC1. Subsequently, using Weighted Gene Co-expression Network Analysis (WGCNA), we discovered that SYNPO2L can regulate COL10A1, mediating the actions of Cancer-Associated Fibroblasts. SYNPO2L promotes the secretion of COL10A1 and the infiltration of tumor-associated fibroblasts, thereby facilitating Epithelial-Mesenchymal Transition (EMT) in tumor cells and making them more prone to distant metastasis.

Asunto(s)

Fibroblastos Asociados al Cáncer , Colágeno Tipo X , Neoplasias Pulmonares , Metiltransferasas , ARN Mensajero , Animales , Humanos , Ratones , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Línea Celular Tumoral , Colágeno Tipo X/metabolismo , Colágeno Tipo X/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metiltransferasas/metabolismo , Metiltransferasas/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética

RESUMEN

Background: The regulation of cancer stem cells (CSCs) is influenced by RNA-binding proteins (RBPs). The present study sought to investigate the role of NOVA2 in the processes of self-renewal, carcinogenesis, and lenvatinib resistance in liver CSCs. Methods: Neuro-oncological ventral antigen 2 (NOVA2) expression in liver CSCs was examined by real-time polymerase chain reaction (PCR). In vitro experiments were used to assess the effects of NOVA2 on liver CSC expansion and lenvatinib resistance. Results: In our study, the expression of the RBP NOVA2 was higher in CSCs. NOVA2 also increased the capacity for self-renewal and carcinogenesis of the liver CSCs via the Wnt pathway. Further, suppressing the Wnt pathway leads to desensitization of the hepatocellular carcinoma (HCC) cells that overexpress NOVA2 to apoptosis caused by lenvatinib. Analyzing patient data confirmed reduced levels of NOVA2 and therefore we speculate that NOVA2 may serve as a potential indicator for response to lenvatinib in patients with HCC. Methyltransferase-like 3 (METTL3) and YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1)-dependent N6-methyladenosine (m6A) methylation were linked to upregulation of NOVA2 in HCC. Furthermore, it was shown that the expression of METTL3 was elevated in cellular models of type 2 diabetes mellitus (T2DM). Conclusions: NOVA2 is involved in the process of liver CSC self-renewal and carcinogenesis. In addition, NOVA2 expression may help identify patients with a higher chance of benefiting from lenvatinib treatment and can be a promising therapeutic target for HCC.

RESUMEN

N6-methyladenosine (m6A) modification stands out among various RNA modifications as the predominant form within eukaryotic cells, influencing numerous cellular processes implicated in disease development. m6A modification has gained increasing attention in the development of atherosclerosis and has become a research hotspot in recent years. Programmed cell death (PCD), encompassing apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, plays a pivotal role in atherosclerosis pathogenesis. In this review, we delve into the intricate interplay between m6A modification and diverse PCD pathways, shedding light on their complex association during the onset and progression of atherosclerosis. Clarifying the relationship between m6A and PCD in atherosclerosis is of great significance to provide novel strategies for cardiovascular disease treatment.

Asunto(s)

Adenosina , Apoptosis , Aterosclerosis , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/patología , Animales , Apoptosis/genética , Autofagia/genética , ARN/genética , ARN/metabolismo

RESUMEN

Hepatocellular carcinoma (HCC) is a highly aggressive cancer with a poor prognosis. The molecular mechanisms underlying its development remain unclear. Recent studies have highlighted the crucial role of RNA modifications in HCC progression, which indicates their potential as therapeutic targets and biomarkers for managing HCC. In this review, we discuss the functional role and molecular mechanisms of RNA modifications in HCC through a review and summary of relevant literature, to explore the potential therapeutic agents and biomarkers for diagnostic and prognostic of HCC. This review indicates that specific RNA modification pathways, such as N6-methyladenosine, 5-methylcytosine, N7-methylguanosine, and N1-methyladenosine, are erroneously regulated and are involved in the proliferation, autophagy, innate immunity, invasion, metastasis, immune cell infiltration, and drug resistance of HCC. These findings provide a new perspective for understanding the molecular mechanisms of HCC, as well as potential targets for the diagnosis and treatment of HCC by targeting specific RNA-modifying enzymes or recognition proteins. More than ten RNA-modifying regulators showed the potential for use for the diagnosis, prognosis and treatment decision utility biomarkers of HCC. Their application value for HCC biomarkers necessitates extensive multi-center sample validation in the future. A growing number of RNA modifier inhibitors are being developed, but the lack of preclinical experiments and clinical studies targeting RNA modification in HCC poses a significant obstacle, and further research is needed to evaluate their application value in HCC treatment. In conclusion, this review provides an in-depth understanding of the complex interplay between RNA modifications and HCC while emphasizing the promising potential of RNA modifications as therapeutic targets and biomarkers for managing HCC.

Asunto(s)

Biomarcadores de Tumor , Carcinoma Hepatocelular , Neoplasias Hepáticas , Procesamiento Postranscripcional del ARN , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/diagnóstico , Biomarcadores de Tumor/metabolismo , Animales , Regulación Neoplásica de la Expresión Génica , Pronóstico , ARN/genética , ARN/metabolismo

RESUMEN

Objectives: Ulcerative colitis (UC) is a commonly recurrent inflammatory bowel disease. T helper 17 (Th17)/regulatory T (Treg) cell balance plays an essential role in UC progression. However, it is unknown whether curcumin chitosan microspheres (CCM) regulate the Th17/Treg cell balance. Materials and Methods: The UC mouse model was established by administering 3% dextran sodium sulfate and treated with CCM. The influence of CCM on the Th17/Treg balance was detected using flow cytometry. Cell experiments were conducted to investigate the role and mechanism of IGF2BP1 in Th17/Treg balance. Results: We revealed that CCM demonstrated a significant therapeutic effect on UC. CCM obviously decreased the Th17 cell percentage but boosted the Treg cell percentage in UC mice. CCM remarkably increased the mRNA expression of Foxp3 but suppressed RORγt and interleukin-10 mRNA expression. PCR array of RNA modification-related genes revealed that the m6A binding protein IGF2BP1 was a key molecule in CCM regulation of Th17/Treg balance. IGF2BP1 overexpression dramatically repressed the CCM-induced balance of Th17/Treg cell differentiation. Mechanically, IGF2BP1 targeted LRP5 and regulated LRP5 through m6A modification. Furthermore, the silencing of LRP5 canceled the suppressive effect of IGF2BP1 on Th17/Treg cell percentage. Conclusion: CCM modulated the Th17/Treg balance through IGF2BP1-mediated m6A modification, thereby alleviating UC, and providing new ideas for the treatment of UC.

RESUMEN

The commonest type of eukaryotic RNA modification, N6-methyladenosine (m6A), has drawn increased scrutiny in the context of pathological functioning as well as relevance in determination of RNA stability, splicing, transportation, localization, and translation efficiency. The m6A modification plays an important role in several types of arthritis, especially osteoarthritis and rheumatoid arthritis. Recent studies have reported that m6A modification regulates arthritis pathology in cells, such as chondrocytes and synoviocytes via immune responses and inflammatory responses through functional proteins classified as writers, erasers, and readers. The aim of this review was to highlight recent advances relevant to m6A modification in the context of arthritis pathogenesis and detail underlying molecular mechanisms, regulatory functions, clinical applications, and future perspectives of m6A in arthritis with the aim of providing a foundation for future research directions.

RESUMEN

We previously found that chronic adenosine A1 receptor stimulation with N6-Cyclopentyladenosine increased α-synuclein misfolding and neurodegeneration in a novel α-synucleinopathy model, a hallmark of Parkinson's disease. Here, we aimed to synthesize a dimer caffeine-indan linked by a 6-carbon chain to cross the blood-brain barrier and tested its ability to bind α-synuclein, reducing misfolding, behavioral abnormalities, and neurodegeneration in our rodent model. Behavioral tests and histological stains assessed neuroprotective effects of the dimer compound. A rapid synthesis of the 18F-labeled analogue enabled Positron Emission Tomography and Computed Tomography imaging for biodistribution measurement. Molecular docking analysis showed that the dimer binds to α-synuclein N- and C-termini and the non-amyloid-ß-component (NAC) domain, similar to 1-aminoindan, and this binding promotes a neuroprotective α-synuclein "loop" conformation. The dimer also binds to the orthosteric binding site for adenosine within the adenosine A1 receptor. Immunohistochemistry and confocal imaging showed the dimer abolished α-synuclein upregulation and aggregation in the substantia nigra and hippocampus, and the dimer mitigated cognitive deficits, anxiety, despair, and motor abnormalities. The 18F-labeled dimer remained stable post-injection and distributed in various organs, notably in the brain, suggesting its potential as a Positron Emission Tomography tracer for α-synuclein and adenosine A1 receptor in Parkinson's disease therapy.

Asunto(s)

Cafeína , Receptor de Adenosina A1 , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Animales , Receptor de Adenosina A1/metabolismo , Cafeína/farmacología , Pliegue de Proteína/efectos de los fármacos , Masculino , Ratas , Fármacos Neuroprotectores/farmacología , Simulación del Acoplamiento Molecular , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Tomografía de Emisión de Positrones/métodos , Conducta Animal/efectos de los fármacos

RESUMEN

Our previous research revealed the apoptosis-inhibiting effect of lncRNA FAM230B in gastric cancer (GC). While its role on ferroptosis of GC remain unexplored. In this study, the m6A level and RNA stability regulation of METTL3 on FAM230B was detected by m6A quantification, stability assays, MeRIP, and their interaction was confirmed by RIP, and RNA pull-down assays. The level of ferroptosis was detected by flow cytometry, MDA and GSH level assessments, and electron microscopy. Gene expression was detected by quantitative real-time PCR, western blot, and immunofluorescence. The miR-27a-5p and BTF3 interaction was predicted with TargetScan and confirmed by dual-luciferase assay. Here, elevated levels of METTL3 and FAM230B were observed in GC tissues and cell lines. METTL3 was confirmed to bind with FAM230B RNA. Furthermore, silencing METTL3 reduced FAM230B m6A levels and stability, leading to decreased FAM230B and increased miR-27a-5p expressions. FAM230B knockdown favored ferroptosis and increased BTF3 expression, while its overexpression mitigated erastin-induced ferroptosis in GC cells. Additionally, BTF3 overexpression was found to negate miR-27a-5p's ferroptosis-promoting effects in GC cells. Collectively, our study demonstrates that the m6A modification of FAM230B by METTL3 plays a crucial role in promoting GC progression by reducing ferroptosis, through the modulation of the miR-27a-5p/BTF3 axis.