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OBJECTIVE: Kidney renal clear cell carcinoma (KIRC, ccRCC) is the most common type of renal cancer with high recurrence and mortality. It has long been recognized that Antizyme inhibitor 1 (AZIN1) serves as a pro-oncogenic molecule in multiple cancers. However, the clinicopathological features of AZIN1 in KIRC remain unexplored. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA, TIMER, and GEPIA) were employed for pan-cancer expression and survival analysis of AZIN1, indicating the unique anti-tumor role of AZIN1 in KIRC. The expression and clinical characteristics of AZIN1 in KIRC were further proven via Human Protein Atlas and TCGA. single-sample GSEA was employed to investigate the immune infiltration of AZIN1. Then the downstream pathways were illustrated via the LinkedOmics, Metascape, and Cytoscape databases. The possible upper regulating noncoding RNAs (ncRNAs) were analyzed from five programs-TargetScan, StarBase, miRanda, PITA, and miRmap. RESULTS: AZIN1 is downregulated in KIRC patients. Lower levels of AZIN1 were linked with unfavorable outcomes in KIRC patients. The AZIN1 expression was positively related to immune cell infiltration in KIRC. We also elucidated a possible upstream regulatory ncRNA of AZIN1 in KIRC namely STK4-AS1/AC068338.2-miR-106b-5p-AZIN1 axis as well as the downstream signaling pathways. CONCLUSION: This study illustrated the unique anti-tumor role of AZIN1 in KIRC and provided potential value for guiding immunotherapy and targeted therapy.
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Carcinoma de Células Renales , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Neoplasias Renales/metabolismo , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Masculino , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , FemeninoRESUMEN
BACKGROUND: Follicles are fundamental units of the ovary, regulated intricately during development. Exosomes and ovarian granulosa cells (OGCs) play pivotal roles in follicular development, yet the regulatory mechanisms governing exosomes remain elusive. RESULTS: High-throughput sequencing was employed to evaluate the complete transcript expression profiles of six samples (three porcine ovarian granulosa cells-exosome co-culture samples (GCE) and three porcine ovarian granulosa cells (POGCs) samples). Differential expression analysis revealed 924 lncRNAs, 35 circRNAs, 49 miRNAs, and 9823 mRNAs in the GCE group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated enrichment of differentially expressed transcripts in pathways related to cell proliferation and apoptosis. Furthermore, a ceRNA regulatory network comprising 43 lncRNAs, 6 circRNAs, 11 miRNAs, and 126 mRNAs was constructed based on intergene co-expression correlations. Seven miRNAs associated with cell proliferation and apoptosis regulation were identified within this network, encompassing 92 subnet pairs as candidate genes for further exploration of exosome regulatory mechanisms. Additionally, preliminary verification at the cellular level demonstrated that exosomal miR-200b enhances the viability of POGCs. CONCLUSIONS: Transcriptome analysis unveiled a pivotal candidate ceRNA network potentially implicated in exosome-mediated regulation of granulosa cell proliferation and apoptosis, thereby influencing porcine follicular development. These findings offer insights into the molecular mechanisms of follicular fluid exosome regulation, encompassing both coding and non-coding RNA perspectives.
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It was previously thought that ncRNA could not encode polypeptides, but recent reports have challenged this notion. As research into ncRNA progresses, it is increasingly clear that it serves roles beyond traditional mechanisms, playing significant regulatory roles in various diseases, notably cancer, which is responsible for 70% of human deaths. Numerous studies have highlighted the diverse regulatory mechanisms of ncRNA that are pivotal in cancer initiation and progression. The role of ncRNA-encoded polypeptides in cancer regulation has gained prominence. This article explores the newly identified regulatory functions of these polypeptides in three types of ncRNA-lncRNA, pri-miRNA, and circRNA. These polypeptides can interact with proteins, influence signaling pathways, enhance miRNA stability, and regulate cancer progression, malignancy, resistance, and other clinical challenges. Furthermore, we discuss the evolutionary significance of these polypeptides in the transition from RNA to protein, examining their emergence and conservation throughout evolution.
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Neoplasias , Péptidos , ARN no Traducido , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Péptidos/genética , Péptidos/metabolismo , ARN no Traducido/genética , ARN no Traducido/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Regulación Neoplásica de la Expresión Génica , ARN Circular/genética , ARN Circular/metabolismo , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transducción de SeñalRESUMEN
Targeting non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), has recently emerged as a promising strategy for treating malignancies and other diseases. In recent years, the development of ncRNA-based therapeutics for targeting protein-coding and non-coding genes has also gained momentum. This review systematically examines ongoing and completed clinical trials to provide a comprehensive overview of the emerging landscape of ncRNA-based therapeutics. Significant efforts have been made to advance ncRNA therapeutics to early clinical studies. The most advanced trials have been conducted with small interfering RNAs (siRNAs), miRNA replacement using nanovector-entrapped miRNA mimics, or miRNA silencing by antisense oligonucleotides. While siRNA-based therapeutics have already received FDA approval, miRNA mimics, inhibitors, and lncRNA-based therapeutics are still under evaluation in preclinical and early clinical studies. We critically discuss the rationale and methodologies of ncRNA targeting strategies to illustrate this rapidly evolving field.
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Ensayos Clínicos como Asunto , Neoplasias , ARN no Traducido , Humanos , Neoplasias/genética , Neoplasias/terapia , ARN no Traducido/genética , ARN no Traducido/uso terapéutico , MicroARNs/genética , MicroARNs/uso terapéutico , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Animales , ARN Interferente Pequeño/uso terapéuticoRESUMEN
Circular RNAs (circRNAs) are cardinal players in numerous physiological and pathological processes. CircRNAs play dual roles as tumor suppressors and oncogenes in different oncological contexts, including hepatocellular carcinoma (HCC). Their roles significantly impact the disease at all stages, including initiation, development, progression, invasion, and metastasis, in addition to the response to treatment. In this review, we discuss the biogenesis and regulatory functional roles of circRNAs, as well as circRNA-protein-mRNA ternary complex formation, elucidating the intricate pathways tuned by circRNAs to modulate gene expression and cellular processes through a comprehensive literature search, in silico search, and bioinformatics analysis. With a particular focus on the interplay between circRNAs, epigenetics, and HCC pathology, the article sets the stage for further exploration of circRNAs as novel investigational theranostic agents in the dynamic realm of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Medicina de Precisión , ARN Circular , ARN no Traducido , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Medicina de Precisión/métodos , ARN no Traducido/genética , ARN no Traducido/metabolismo , Simulación por Computador , Regulación Neoplásica de la Expresión Génica , Biología Computacional/métodosRESUMEN
Colorectal cancer (CRC) being one of the most common malignancies, has a significant death rate, especially when detected at an advanced stage. In most cases, the fundamental aetiology of CRC remains unclear despite the identification of several environmental and intrinsic risk factors. Numerous investigations, particularly in the last ten years, have indicated the involvement of epigenetic variables in this type of cancer. The development, progression, and metastasis of CRC are influenced by long non-coding RNAs (lncRNAs), which are significant players in the epigenetic pathways. LncRNAs are implicated in diverse pathological processes in CRC, such as liver metastasis, epithelial to mesenchymal transition (EMT), inflammation, and chemo-/radioresistance. It has recently been determined that CRC cells and tissues exhibit dysregulation of tens of oncogenic and tumor suppressor lncRNAs. Serum samples from CRC patients exhibit dysregulated expressions of several of these transcripts, offering a non-invasive method of detecting this kind of cancer. In this review, we outlined the typical paradigms of the deregulated lncRNA which exert significant role in the underlying molecular mechanisms of CRC initiation and progression. We comprehensively discuss the role of lncRNAs as innovative targets for CRC prognosis and treatment.
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PIWI-interacting RNAs (piRNAs) have received a lot of attention for their functions in cancer research. This class of short non-coding RNAs (ncRNA) has roles in genomic stability, chromatin remodeling, messenger RNA (mRNA) integrity, and genome structure. We summarized the mechanisms underlying the biogenesis and regulatory molecular functions of piRNAs. Among all piRNAs studied in cancer, this review offers a comprehensive analysis of the emerging roles of piR-823 in various types of cancer, including colorectal, gastric, liver, breast, and renal cancers, as well as multiple myeloma. piR-823 has emerged as a crucial modulator of various cancer hallmarks through regulating multiple pathways. In the current review, we analyzed several databases and conducted an extensive literature search to explore the influence of piR-823 in carcinogenesis in addition to describing the potential application of piR-823 as prognostic and diagnostic markers as well as the therapeutic potential toward ncRNA precision.
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Diabetic retinopathy (DR), a significant and vision-endangering complication associated with diabetes mellitus, constitutes a substantial portion of acquired instances of preventable blindness. The progression of DR appears to prominently feature the loss of retinal cells, encompassing neural retinal cells, pericytes, and endothelial cells. Therefore, mitigating the apoptosis of retinal cells in DR could potentially enhance the therapeutic approach for managing the condition by suppressing retinal vascular leakage. Recent advancements have highlighted the crucial regulatory roles played by non-coding RNAs (ncRNAs) in diverse biological processes. Recent advancements have highlighted that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs), act as central regulators in a wide array of biogenesis and biological functions, exerting control over gene expression associated with histogenesis and cellular differentiation within ocular tissues. Abnormal expression and activity of ncRNAs has been linked to the regulation of diverse cellular functions such as apoptosis, and proliferation. This implies a potential involvement of ncRNAs in the development of DR. Notably, ncRNAs and apoptosis exhibit reciprocal regulatory interactions, jointly influencing the destiny of retinal cells. Consequently, a thorough investigation into the complex relationship between apoptosis and ncRNAs is crucial for developing effective therapeutic and preventative strategies for DR. This review provides a fundamental comprehension of the apoptotic signaling pathways associated with DR. It then delves into the mutual relationship between apoptosis and ncRNAs in the context of DR pathogenesis. This study advances our understanding of the pathophysiology of DR and paves the way for the development of novel therapeutic strategies.
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Apoptosis , Retinopatía Diabética , ARN no Traducido , Transducción de Señal , Retinopatía Diabética/genética , Retinopatía Diabética/metabolismo , Retinopatía Diabética/terapia , Humanos , Apoptosis/genética , Transducción de Señal/genética , Animales , ARN no Traducido/genética , ARN no Traducido/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Retina/metabolismo , Retina/patologíaRESUMEN
Cis-regulatory elements (CREs) are integral to the spatiotemporal and quantitative expression dynamics of target genes, thus directly influencing phenotypic variation and evolution. However, many of these CREs become highly susceptible to transcriptional silencing when in a transgenic state, particularly when organised as tandem repeats. We investigated the mechanism of this phenomenon and found that three of the six selected flower-specific CREs were prone to transcriptional silencing when in a transgenic context. We determined that this silencing was caused by the ectopic expression of non-coding RNAs (ncRNAs), which were processed into 24-nt small interfering RNAs (siRNAs) that drove RNA-directed DNA methylation (RdDM). Detailed analyses revealed that aberrant ncRNA transcription within the AGAMOUS enhancer (AGe) in a transgenic context was significantly enhanced by an adjacent CaMV35S enhancer (35Se). This particular enhancer is known to mis-activate the regulatory activities of various CREs, including the AGe. Furthermore, an insertion of 35Se approximately 3.5 kb upstream of the AGe in its genomic locus also resulted in the ectopic induction of ncRNA/siRNA production and de novo methylation specifically in the AGe, but not other regions, as well as the production of mutant flowers. This confirmed that interactions between the 35Se and AGe can induce RdDM activity in both genomic and transgenic states. These findings highlight a novel epigenetic role for CRE-CRE interactions in plants, shedding light on the underlying forces driving hypermethylation in transgenes, duplicate genes/enhancers, and repetitive transposons, in which interactions between CREs are inevitable.
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This review comprehensively investigates the intricate interplay between small non-coding RNAs (sncRNAs) and pancreatic ductal adenocarcinoma (PDAC), a devastating malignancy with limited therapeutic options. Our analysis reveals the pivotal roles of sncRNAs in various facets of PDAC biology, spanning diagnosis, pathogenesis, drug resistance, and therapeutic strategies. sncRNAs have emerged as promising biomarkers for PDAC, demonstrating distinct expression profiles in diseased tissues. sncRNA differential expression patterns, often detectable in bodily fluids, hold potential for early and minimally invasive diagnostic approaches. Furthermore, sncRNAs exhibit intricate involvement in PDAC pathogenesis, regulating critical cellular processes such as proliferation, apoptosis, and metastasis. Additionally, mechanistic insights into sncRNA-mediated pathogenic pathways illuminate novel therapeutic targets and interventions. A significant focus of this review is dedicated to unraveling sncRNA mechanisms underlying drug resistance in PDAC. Understanding these mechanisms at the molecular level is imperative for devising strategies to overcome drug resistance. Exploring the therapeutic landscape, we discuss the potential of sncRNAs as therapeutic agents themselves as their ability to modulate gene expression with high specificity renders them attractive candidates for targeted therapy. In summary, this review integrates current knowledge on sncRNAs in PDAC, offering a holistic perspective on their diagnostic, pathogenic, and therapeutic relevance. By elucidating the roles of sncRNAs in PDAC biology, this review provides valuable insights for the development of novel diagnostic tools and targeted therapeutic approaches, crucial for improving the prognosis of PDAC patients.
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N6-methyladenosine (m6A) is one of the most common internal modifications in eukaryotic RNA. The presence of m6A on transcripts can affect a series of fundamental cellular processes, including mRNA splicing, nuclear transportation, stability, and translation. The m6A modification is introduced by m6A methyltransferases (writers), removed by demethylases (erasers), and recognized by m6A-binding proteins (readers). Current research has demonstrated that m6A methylation is involved in the regulation of malignant phenotypes in tumors by controlling the expression of cancer-related genes. Non-coding RNAs (ncRNAs) are a diverse group of RNA molecules that do not encode proteins and are widely present in the human genome. This group includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and PIWI interaction RNAs (piRNAs). They function as oncogenes or tumor suppressors through various mechanisms, regulating the initiation and progression of cancer. Previous studies on m6A primarily focused on coding RNAs, but recent discoveries have revealed the significant regulatory role of m6A in ncRNAs. Simultaneously, ncRNAs also exert their influence by modulating the stability, splicing, translation, and other biological processes of m6A-related enzymes. The interplay between m6A and ncRNAs collectively contributes to the occurrence and progression of malignant tumors in humans. This review provides an overview of the interactions between m6A regulatory factors and ncRNAs and their impact on tumors.
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Alzheimer's disease (AD) is the leading cause of dementia globally, having a pathophysiology that is complex and multifactorial. Recent findings highlight the significant role of non-coding RNAs (ncRNAs), specifically microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs) in the molecular mechanisms underlying AD. These ncRNAs are involved in critical biological processes such as cell proliferation, apoptosis, oxidative stress, amyloid-beta aggregation, tau phosphorylation, neuroinflammation, and autophagy, which are pivotal in AD development and progression. This systematic review aims to consolidate current scientific knowledge on the role of ncRNAs in AD, making it the first to encompass the four types of ncRNAs associated with the disease. Our comprehensive search and analysis reveal that ncRNAs not only play crucial roles in the pathogenesis of AD but also hold potential as biomarkers for its early detection and as novel therapeutic targets. Specifically, the findings underscore the significance of miRNAs in regulating genes involved in key AD pathways such as activin receptor signaling pathway, actomyosin contractile ring organization, and advanced glycation endproducts-receptor advanced glycation endproducts (AGE-RAGE) signaling pathway. This review also highlights the potential of ncRNAs in unveiling novel diagnostic and therapeutic strategies, emphasizing the need for further research to validate their clinical utility. Our systematic exploration provides a foundation for future bioinformatic analyses and the development of ncRNA-based precision medicine approaches for AD, offering new insights into the disease's molecular pathology and paving the way for innovative treatment strategies. Systematic review registration: PROSPERO, https://www.crd.york.ac.uk/prospero/, CRD42022355307.
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Cancer treatment has always been a challenge for humanity. The inadequacies of current technologies underscore the limitations of our efforts against this disease. Nevertheless, the advent of targeted therapy has introduced a promising avenue, furnishing us with more efficacious tools. Consequently, researchers have turned their attention toward epigenetics, offering a novel perspective in this realm. The investigation of epigenetics has brought RNA readers to the forefront, as they play pivotal roles in recognizing and regulating RNA functions. Recently, the development of inhibitors targeting these RNA readers has emerged as a focal point in research and holds promise for further strides in targeted therapy. In this review, we comprehensively summarize various types of inhibitors targeting RNA readers, including non-coding RNA (ncRNA) inhibitors, small-molecule inhibitors, and other potential inhibitors. We systematically elucidate their mechanisms in suppressing cancer progression by inhibiting readers, aiming to present inhibitors of readers at the current stage and provide more insights into the development of anticancer drugs.
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Antineoplásicos , Epigénesis Genética , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Epigénesis Genética/efectos de los fármacos , ARN no Traducido/genética , ARN/metabolismo , AnimalesRESUMEN
Circular RNAs (CircRNAs) are non-coding RNAs (ncRNAs) characterized by a stable circular structure that regulates gene expression at both transcriptional and post-transcriptional levels. They play diverse roles, including protein interactions, DNA methylation modification, protein-coding potential, pseudogene creation, and miRNA sponging, all of which influence various physiological processes. CircRNAs are often highly expressed in brain tissues, and their levels vary with neural development, suggesting their significance in nervous system diseases such as gliomas. Research has shown that circRNA expression related to the PI3K pathway correlates with various clinical features of gliomas. There is an interact between circRNAs and the PI3K pathway to regulate glioma cell processes such as proliferation, differentiation, apoptosis, inflammation, angiogenesis, and treatment resistance. Additionally, PI3K pathway-associated circRNAs hold potential as biomarkers for cancer diagnosis, prognosis, and treatment. In this study, we reviewed the latest advances in the expression and cellular roles of PI3K-mediated circRNAs and their connections to glioma carcinogenesis and progression. We also highlighted the significance of circRNAs as diagnostic and prognostic biomarkers and therapeutic targets in glioma.
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Neoplasias Encefálicas , Progresión de la Enfermedad , Glioma , Fosfatidilinositol 3-Quinasas , ARN Circular , Transducción de Señal , Humanos , Glioma/patología , Glioma/genética , Glioma/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Transducción de Señal/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , AnimalesRESUMEN
Pest control heavily relies on chemical pesticides has been going on for decades. However, the indiscriminate use of chemical pesticides often results in the development of resistance in pests. Almost all pests have developed some degree of resistance to pesticides. Research showed that the mechanisms of insecticide resistance in insects encompass metabolic resistance, behavioral resistance, penetration resistance and target-site resistance. Research on the these mechanisms has been mainly focused on the cis-regulatory or trans-regulatory for the insecticide resistance-related genes, with less attention paid to non-coding RNAs (ncRNAs), such as microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA). There has been increased studies focus on understanding how these ncRNAs are involved in post-transcriptional regulation of insecticide resistance-related genes. Besides, the formatted endogenous RNA (ceRNA) regulatory networks (lncRNA/circRNA-miRNA-mRNA) has been identified as a key player in governing insect resistance formation. This review delves into the functions and underlying mechanisms of miRNA, lncRNA, and circRNA in regulating insect resistance. ncRNAs orchestrate insect resistance by modulating the expression of detoxification enzyme genes, insecticide target genes, as well as receptor genes, effectively regulating both target-site, metabolic and penetration resistance in insects. It also explores the regulatory mechanisms of ceRNA networks in the development of resistance. By enhancing our understanding of the mechanisms of ncRNAs in insecticide resistance, it will not only provide valuable insights into the new mechanisms of insecticide resistance but also help to enrich new directions in ncRNAs gene regulation research.
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DNA methylation plays a pivotal role in cancer. The ubiquitous contaminant perfluorooctanesulfonic acid (PFOS) has been epidemiologically associated with breast cancer, and can induce proliferation and malignant transformation of normal human breast epithelial cells (MCF-10A), but the information about its effect on DNA methylation is sparse. The aim of this study was to characterize the whole-genome methylome effects of PFOS in our breast cell model and compare the findings with previously demonstrated DNA methylation alterations in breast tumor tissues. The DNA methylation profile was assessed at single CpG resolution in MCF-10A cells treated with 1 µM PFOS for 72 h by using Enzymatic Methyl sequencing (EM-seq). We found 12,591 differentially methylated CpG-sites and 13,360 differentially methylated 100 bp tiles in the PFOS exposed breast cells. These differentially methylated regions (DMRs) overlapped with 2406 genes of which 494 were long non-coding RNA and 1841 protein coding genes. We identified 339 affected genes that have been shown to display altered DNA methylation in breast cancer tissue and several other genes related to cancer development. This includes hypermethylation of GACAT3, DELEC1, CASC2, LCIIAR, MUC16, SYNE1 and hypomethylation of TTN and KMT2C. DMRs were also found in estrogen receptor genes (ESR1, ESR2, ESRRG, ESRRB, GREB1) and estrogen responsive genes (GPER1, EEIG1, RERG). The gene ontology analysis revealed pathways related to cancer phenotypes such as cell adhesion and growth. These findings improve the understanding of PFOS's potential role in breast cancer and illustrate the value of whole-genome methylome analysis in uncovering mechanisms of chemical effects, identifying biomarker candidates, and strengthening epidemiological associations, potentially impacting risk assessment.
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Ácidos Alcanesulfónicos , Neoplasias de la Mama , Metilación de ADN , Fluorocarburos , Humanos , Ácidos Alcanesulfónicos/toxicidad , Fluorocarburos/toxicidad , Metilación de ADN/efectos de los fármacos , Neoplasias de la Mama/genética , Femenino , EpigenomaRESUMEN
Treatment of non-small-cell lung cancer (NSCLC) patients possessing EGFR-activating mutations with tyrosine kinase inhibitors (TKIs) can confer an initial promising response. However, TKI resistance inevitably arises. Numerous TKI resistance mechanisms are identified including EGFR secondary mutations, bypass receptor tyrosine kinase (RTK) signaling, and cellular transition e.g. epithelial-mesenchymal transition (EMT). To increase the knowledge of TKI resistance we performed an epigenetic screen to identify small non-coding (nc) genes with DNA methylation alterations in HCC827 NSCLC EGFR-mutated cells with acquired TKI resistance. We analyzed Infinium Methylation EPIC 850K Array data for DNA methylation changes present in both TKI-resistant HCC827 cells with EMT and MET-amplification. Hereby, we identified that the polymorphic maternal imprinted gene nc886 (vtRNA2-1) has a decrease in promoter DNA methylation in TKI-resistant cells. This epigenetic change was associated with an increase in the expression of nc886. The induction of EMT did not affect nc886 expression. CRISPR/Cas9-mediated distortion of the nc886 sequence increased the sensitivity of HCC827 cells towards TKI. Finally, nc886 sequence distortion hindered MET RTK activation and instead was EMT the endpoint TKI resistance mechanism. In conclusion, the expression of nc886 contributes to TKI resistance in the HCC827 NSCLC cell line by supporting cell survival and selection of the endpoint TKI resistance mechanism. We propose DNA methylation and expression changes for nc886 to constitute a novel TKI resistance contributing mechanism in NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Metilación de ADN , Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Mutación , Inhibidores de Proteínas Quinasas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , ARN no Traducido/genética , ARN no Traducido/metabolismo , Epigénesis Genética/efectos de los fármacosRESUMEN
The substantial heterogeneity exhibited by head and neck cancer (HNC), encompassing diverse cellular origins, anatomical locations, and etiological contributors, combined with the prevalent late-stage diagnosis, poses significant challenges for clinical management. Genomic sequencing endeavors have revealed extensive alterations in key signaling pathways that regulate cellular proliferation and survival. Initiatives to engineer therapies targeting these dysregulated pathways are underway, with several candidate molecules progressing to clinical evaluation phases, including FDA approval for agents like the EGFR-targeting monoclonal antibody cetuximab for K-RAS wild-type, EGFR-mutant HNSCC treatment. Non-coding RNAs (ncRNAs), owing to their enhanced stability in biological fluids and their important roles in intracellular and intercellular signaling within HNC contexts, are now recognized as potent biomarkers for disease management, catalyzing further refined diagnostic and therapeutic strategies, edging closer to the personalized medicine desideratum. Enhanced comprehension of the genomic and immunological landscapes characteristic of HNC is anticipated to facilitate a more rigorous assessment of targeted therapies benefits and limitations, optimize their clinical deployment, and foster innovative advancements in treatment approaches. This review presents an update on the molecular mechanisms and mutational spectrum of HNC driving the oncogenesis of head and neck malignancies and explores their implications for advancing diagnostic methodologies and precision therapeutics.
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BACKGROUND: Occlusal disharmony (OD) may induce anxiety-like behaviours; however, the underlying mechanism remains unclear. Herein, we explored the expression profiles of non-coding RNAs (ncRNAs), along with their biological function and regulatory network, in anxiety-like behaviour induced by OD. MATERIALS AND METHODS: Occlusal disharmony was produced by anterior crossbite of C57BL/6 mice. Behavioural tests, corticosterone (CORT) and serotonin (5-HT) levels were used to measure anxiety. In addition, RNA sequencing was used to screen all differentially expressed (DE) ncRNAs. Moreover, the RNA-binding proteins interacting with ncRNAs were predicted by the ENCORI database and confirmed using western blots. RESULTS: The significant differences in behavioural tests and CORT suggested the successful induction of anxiety-like behaviour by OD. In OD mice, ncRNAs were significantly dysregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that the DE ncRNAs were enriched in anxiety-related pathways. CircRNA10039 was upregulated, and PTBP1 was predicted to interact with circRNA10039. In addition, KEGG pathway analysis showed that PTBP1 may be associated with messenger RNA biogenesis and spliceosomes. CONCLUSION: OD induced by anterior crossbite can lead to the anxiety-like behaviours. During this process, ncRNA also changes. CircRNA10039 and PTBP1 may play a role in OD-induced anxiety-like behaviours.