RESUMO
Chronic wounds are a major complication in patients with diabetes. Here, we identify a therapeutic circRNA and load it into small extracellular vesicles (sEVs) to treat diabetic wounds in preclinical models. We show that circCDK13 can stimulate the proliferation and migration of human dermal fibroblasts and human epidermal keratinocytes by interacting with insulin-like growth factor 2 mRNA binding protein 3 in an N6-Methyladenosine-dependent manner to enhance CD44 and c-MYC expression. We engineered sEVs that overexpress circCDK13 and show that local subcutaneous injection into male db/db diabetic mouse wounds and wounds of streptozotocin-induced type I male diabetic rats could accelerate wound healing and skin appendage regeneration. Our study demonstrates that the delivery of circCDK13 in sEVs may present an option for diabetic wound treatment.
Assuntos
Diabetes Mellitus Experimental , Vesículas Extracelulares , Fibroblastos , Queratinócitos , RNA Circular , Cicatrização , Animais , Humanos , Masculino , Camundongos , Ratos , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Vesículas Extracelulares/química , Fibroblastos/efeitos dos fármacos , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/genética , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , RNA Circular/farmacologia , RNA Circular/uso terapêutico , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacosRESUMO
The role of circular RNAs (circRNAs) in neuropathic pain is linked to the fundamental physiological mechanisms involved. However, the exact function of circRNAs in the context of neuropathic pain is still not fully understood. The functional impact of circGRIN2B on the excitability of dorsal root ganglion (DRG) neurons was investigated using siRNA or overexpression technology in conjunction with fluorescence in situ hybridization and whole-cell patch-clamp technology. The therapeutic efficacy of circGRIN2B in treating neuropathic pain was confirmed by assessing the pain threshold in a chronic constrictive injury (CCI) model. The interaction between circGRIN2B and NF-κB was examined through RNA pulldown, RIP, and mass spectrometry assays. CircGRIN2B knockdown significantly affected the action potential discharge frequency and the sodium-dependent potassium current flux (SLICK) in DRG neurons. Furthermore, knockdown of circGRIN2B dramatically reduced the SLICK channel protein and mRNA expression in vivo and in vitro. Our research confirmed the interaction between circGRIN2B and NF-κB. These findings demonstrated that circGRIN2B promotes the transcription of the SLICK gene by binding to NF-κB. In CCI rat models, the overexpression of circGRIN2B has been shown to hinder the progression of neuropathic pain, particularly by reducing mechanical and thermal hyperalgesia. Additionally, this upregulation significantly diminished the levels of the inflammatory cytokines IL-1ß, IL-6, and TNF-α in the DRG. Upon reviewing these findings, it was determined that circGRIN2B may mitigate the onset of neuropathic pain by modulating the NF-κB/SLICK pathway.
Assuntos
NF-kappa B , Neuralgia , Ratos , Animais , NF-kappa B/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Circular/uso terapêutico , Ratos Sprague-Dawley , Hibridização in Situ Fluorescente , Neuralgia/terapia , Neuralgia/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Gânglios Espinais/metabolismoRESUMO
Colorectal cancer (CRC) is recognized as one of the most common gastrointestinal malignancies across the globe. Despite significant progress in designing novel treatments for CRC, there is a pressing need for more effective therapeutic approaches. Unfortunately, many patients undergoing chemotherapy develop drug resistance, posing a significant challenge for cancer treatment. Non-coding RNAs (ncRNAs) have been found to play crucial roles in CRC development and its response to chemotherapy. However, there are still gaps in our understanding of interactions among various ncRNAs, such as long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs). These ncRNAs can act as either oncogenes or tumour suppressors, affecting numerous biological functions in different cancers including CRC. A class of ncRNA molecules known as competitive endogenous RNAs (ceRNAs) has emerged as a key player in various cellular processes. These molecules form networks through lncRNA/miRNA/mRNA and circRNA/miRNA/mRNA interactions. In CRC, dysregulation of ceRNA networks has been observed across various cellular processes, including proliferation, apoptosis and angiogenesis. These dysregulations are believed to play a significant role in the progression of CRC and, in certain instances, may contribute to the development of chemoresistance. Enriching our knowledge of these dysregulations holds promise for advancing the field of diagnostic and therapeutic modalities for CRC. In this review, we discuss lncRNA- and circRNA-associated ceRNA networks implicated in the emergence and advancement of drug resistance in colorectal carcinogenesis.
Assuntos
Neoplasias Colorretais , MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Circular/genética , RNA Circular/uso terapêutico , RNA Endógeno Competitivo , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , MicroRNAs/uso terapêutico , RNA não Traduzido/genética , RNA Mensageiro/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologiaRESUMO
Colorectal cancer (CRC) poses a substantial global challenge, necessitating a deeper understanding of the molecular underpinnings governing its onset and progression. The transforming growth factor beta (TGF-ß) network has been a well-recognized cornerstone in advancing CRC. Nevertheless, a recent study has highlighted the growing importance of non-coding RNAs (ncRNAs) in this context. This comprehensive review aims to present an extensive examination of the interaction between ncRNAs and TGF-signaling. Noncoding RNAs (ncRNAs), encompassing circular RNAs (circRNAs), long-ncRNAs (lncRNAs), and microRNAs (miRNAs), have surfaced as pivotal modulators governing various aspects of TGF-ß signaling. MiRNAs have been discovered to target elements within the TGF-ß signaling, either enhancing or inhibiting signaling, depending on the context. LncRNAs have been associated with CRC progression, functioning as miRNA sponges or directly influencing TGF-ß pathway elements. Even circRNAs, a relatively recent addition to the ncRNA family, have impacted CRC, affecting TGF-ß signaling through diverse mechanisms. This review encompasses recent progress in comprehending specific ncRNAs involved in TGF-ß signaling, their functional roles, and their clinical relevance in CRC. We investigate the possibility of ncRNAs as targets for detection, prognosis, and therapy. Additionally, we explore the interaction of TGF-ß and other pathways in CRC and the role of ncRNAs within this intricate network. As we unveil the intricate regulatory function of ncRNAs in the TGF-ß signaling in CRC, we gain valuable insights into the disease's pathogenesis. Incorporating these discoveries into clinical settings holds promise for more precise diagnosis, prognosis, and targeted therapeutic approaches, ultimately enhancing the care of CRC patients. This comprehensive review underscores the ever-evolving landscape of ncRNA research in CRC and the potential for novel interventions in the battle against this formidable disease.
Assuntos
Neoplasias Colorretais , MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , RNA Circular/genética , RNA Circular/uso terapêutico , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , RNA não Traduzido/genética , MicroRNAs/metabolismo , Neoplasias Colorretais/patologiaRESUMO
Mycoplasma pneumoniae (MP) is primarily recognized as a respiratory pathogen that causes community-acquired pneumonia, which can lead to acute upper and lower airway inflammation and extrapulmonary syndrome. Refractory pneumonia caused by MP can cause severe complications and even be life-threatening, particularly in infants and the elderly. It is well-known that non-coding RNAs (ncRNAs) represented by miRNAs, lncRNAs and circRNAs have been manifested to be widely involved in the regulation of gene expression. Growing evidence indicates that these ncRNAs have distinct differentiated expression in MP infection and affect multiple biological processes, playing an indispensable role in the initiation and promotion of MP infection. However, the epigenetic mechanisms involved in the development of MP infection remain unclear. This article reviews the mechanisms by which miRNAs, lncRNAs, and circRNAs mediate MP infection, such as inflammatory responses, apoptosis and pulmonary fibrosis. Focusing on miRNAs, lncRNAs and circRNAs associated with MP infection could provide new insights into this disease's early diagnosis and therapeutic approaches.
Assuntos
MicroRNAs , Pneumonia por Mycoplasma , RNA Longo não Codificante , Lactente , Humanos , Idoso , Pneumonia por Mycoplasma/tratamento farmacológico , Pneumonia por Mycoplasma/genética , MicroRNAs/genética , RNA Circular/genética , RNA Circular/uso terapêutico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/uso terapêutico , Mycoplasma pneumoniae/genéticaRESUMO
Recent advances in the RNA delivery system have facilitated the development of a separate field of RNA therapeutics, with modalities including mRNA, microRNA (miRNA), antisense oligonucleotide (ASO), small interfering RNA, and circular (circRNA) that have been incorporated into oncology research. The main advantages of the RNA-based modalities are high flexibility in designing RNA and rapid production for clinical screening. It is challenging to eliminate tumors by tackling a single target in cancer. In the era of precision medicine, RNA-based therapeutic approaches potentially constitute suitable platforms for targeting heterogeneous tumors that possess multiple sub-clonal cancer cell populations. In this review, we discussed how synthetic coding and non-coding RNAs, such as mRNA, miRNA, ASO, and circRNA, can be applied in the development of therapeutics. SIGNIFICANCE STATEMENT: With development of vaccines against coronavirus, RNA-based therapeutics have received attention. Here, the authors discuss different types of RNA-based therapeutics potentially effective against tumor that are highly heterogeneous giving rise to resistance and relapses to the conventional therapeutics. Moreover, this study summarized recent findings suggesting combination approaches of RNA therapeutics and cancer immunotherapy.
Assuntos
MicroRNAs , Neoplasias , Humanos , RNA/genética , RNA Circular/genética , RNA Circular/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , RNA MensageiroRESUMO
BACKGROUND: Current treatments for lung cancer have their own deficiencies, such as severe adverse effect. Therefore, more safe and effective drugs are needed. PURPOSE: Fuzheng Kang-Ai (FZKA for short) has been applied as an adjuvant treatment in advanced Non-Small Cell Lung Cancer (NSCLC) patients for decades in China, showing a definitive effect with minimal toxicities. However, the underlying mechanism is yet to be identified. STUDY DESIGN: Both in vitro and in vivo experiments were performed in this study to identify the exact mechanism by which FZKA inhibits NSCLC cell proliferation. METHODS: MTT and CCK-8 assays were used to detect cell viability. Xenograft model was performed for in vivo experiments. CircRNA and miRNA sequencing were used to find the differentially expressed circRNAs and miRNAs, respectively. qRT-PCR was performed to check the expression levels of circRNA, miRNA and mRNA. BaseScope was carried out to observe the expression of circRNA in situ. Actinomycin D and RNase R experiments were done to show the stability of circRNA. Nuclear-cytoplasmic fractionation and FISH were used to identify the localization of circRNA and miRNA. Pull-down, RIP, and luciferase activity assays were performed to show the biding ability of circRNA, miRNA and target proteins. Flow cytometry was done to observe cell apoptosis. Western blot and IHC were done to detect the protein expression. TCGA database was used to analyze the survival rate. RESULTS: FZKA inhibits NSCLC cell proliferation both in vitro and in vivo. Hsa_circ_0048091 and hsa-miR-378g were the most differentially expressed circRNA and miRNA, respectively, after FZKA treatment. Silencing hsa_circ_0048091 and overexpressing hsa-miR-378g promoted cell proliferation and reversed the inhibition effect of FZKA on NSCLC, respectively. Hsa-miR-378g was sponged by hsa_circ_0048091, and the overexpression of miR-378g reversed the inhibition effect of hsa_ circ_0048091 on NSCLC. ARRDC3, as a target of hsa-miR-378g, was increased by FZKA treatment. Silencing ARRDC3 reversed both the inhibition effect of FZKA and miR-378g inhibitor on NSCLC. CONCLUSION: This study, for the first time, has established the function of hsa_circ_0048091, hsa- miR-378g, and ARRDC3 in lung cancer. It also shows that FZKA inhibits NSCLC cell proliferation through hsa_circ_0048091/hsa-miR-378g/ARRDC3 pathway, uncovering a novel mechanism by which FZKA controls human NSCLC cell growth.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/genética , RNA Circular/genética , RNA Circular/metabolismo , RNA Circular/uso terapêutico , Linhagem Celular Tumoral , MicroRNAs/genética , Proliferação de Células/genética , Arrestinas/metabolismo , Arrestinas/uso terapêuticoRESUMO
Dysregulation of circular RNAs (circRNAs) has been reported to be functionally associated with chronic pain, but it is unknown whether and how circRNAs participate in visceral hypersensitivity. The expression of circKcnk9 was increased in spinal neurons of irritable bowel syndrome (IBS)-like rats. ShcircKcnk9 attenuated visceral hypersensitivity and inhibited c-Fos expression in IBS-like rats, whereas overexpression of spinal circKcnk9 induced visceral hypersensitivity and increased c-Fos expression in control rats. Furthermore, circKcnk9 was found to act as a miR-124-3p sponge. MiR-124-3p antagomir restored pain responses downregulated by shcircKcnk9 in IBS-like rats. Finally, the signal transducer and activator of transcription 3 (STAT3), validated as a target of miR-124-3p, could play a critical role in visceral hypersensitivity by regulating NSF/GluR2. PERSPECTIVE: Spinal circKcnk9 functions as a miR-124-3p sponge to promote visceral hypersensitivity by regulating the STAT3/NSF/GluR2 pathway. This pathway might provide a novel epigenetic mechanism of visceral hypersensitivity and a potential circRNA therapeutic target for IBS.
Assuntos
Hipersensibilidade , Síndrome do Intestino Irritável , MicroRNAs , Dor Visceral , Animais , Ratos , Hipersensibilidade/complicações , Síndrome do Intestino Irritável/complicações , MicroRNAs/genética , RNA Circular/uso terapêutico , Dor Visceral/tratamento farmacológico , Doença CrônicaRESUMO
Exosomes are multifunctional regulators of intercellular communication by carrying various messages under both physiological and pathological status of cancer patients. Accumulating studies have identified the presence of circular RNAs (circRNAs) in exosomes with crucial regulatory roles in diverse pathophysiological processes. Exosomal circRNAs derived from donor cells can modulate crosstalk with recipient cells locally or remotely to enhance cancer development and propagation, and play crucial roles in the tumor microenvironment (TME), leading to significant enhancement of tumor immunity, metabolism, angiogenesis, drug resistance, epithelial mesenchymal transition (EMT), invasion and metastasis. In this review, we describe the advances of exosomal circRNAs and their roles in modulating cancer hallmarks, especially those in the TME. Moreover, clinical application potential of exosomal circRNAs in cancer diagnosis and therapy are highlighted, bridging the gap between basic knowledge and clinical practice.
Assuntos
Exossomos/metabolismo , Neoplasias , RNA Circular/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Animais , Humanos , Neoplasias/diagnóstico , Neoplasias/terapiaRESUMO
Exosomes, a special type of membrane-bound extracellular vesicle regarded as an ideal carrier for intercellular messages, play an essential role in intercellular communication both locally and systematically. Recent studies have reported that circular RNAs (circRNAs), members of the noncoding RNA family, are abundant and stable in exosomes. As an essential mediator of intercellular communication within cancer cells or between cancer cells and noncancerous cells, exosomal circRNAs participate in multiple aspects of cancer. In this review, we summarize the biogenesis, properties and functions of exosomal circRNAs. In particular, we describe their intercellular transfer in the tumour microenvironment and associate their biological functions with different phenotypes of cancer. Finally, we discuss potential clinical applications in the future.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias/tratamento farmacológico , RNA Circular/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Comunicação Celular/genética , Exossomos/genética , Humanos , RNA Circular/uso terapêuticoRESUMO
Gemcitabine is the first-line treatment for patients with pancreatic cancer (PC), yet most patients develop resistance to gemcitabine. Recent studies showed that circular RNAs (circRNAs) have important regulatory roles in PC progression and chemoresistance. In this study, the ability of circRNA circ_0092367 to enhance gemcitabine efficacy was tested and the underlying molecular mechanism of circ_0092367 was investigated. The expression levels of circ_0092367, miR-1206, and ESRP1 were measured using qRT-PCR experiments. The effects of circ_0092367, miR-1206, and ESRP1 on PC cell lines exposed to gemcitabine were examined by CCK-8 assays. We performed luciferase assays to determine the relationship between circ_0092367 and miR-1206 and between miR-1206 and ESRP1. We demonstrated that circ_0092367 was significantly downregulated in PC tissues and cell lines, and a high expression of circ_0092367 was associated with improved survival in patients with PC. Gain- and loss-of-function assays revealed that circ_0092367 inhibited epithelial-mesenchymal transition (EMT) phenotypes and sensitized PC cells to gemcitabine treatment in vitro and in vivo. Cytoplasmic circ_0092367 could directly repress the levels of miR-1206 and thus upregulate the expression of ESRP1, thereby inhibiting EMT and enhancing the sensitivity of PC cells to gemcitabine treatment. Our findings show that circ_0092367 plays a crucial role in sensitizing PC cells to gemcitabine by modulating the miR-1206/ESRP1 axis, highlighting its potential as a valuable therapeutic target in PC patients.
Assuntos
Desoxicitidina/análogos & derivados , MicroRNAs/genética , Neoplasias Pancreáticas , RNA Circular/fisiologia , Proteínas de Ligação a RNA/genética , Animais , Células Cultivadas , Desoxicitidina/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , RNA Circular/uso terapêutico , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
BACKGROUND: Though circular RNAs, new non-coding RNA classes have demonstrated that they have an essential role in the initiation as well as development of CRC (colorectal cancer), whereas in CRC the function and mechanism of hsa_circ_0001666 are less known. METHODS: Hsa_circ_0001666 was identified by bioinformatics analysis of a circRNA microarray from the GEO database, and its expression in both CRC cell lines and tissues was analysed. A series of in vitro along with in vivo experiments were carried out for exploring the hsa_circ_0001666 functions, including transwell, wound healing, flow cytometry, colony formation, Edu, CCK-8, soft agar colony formation, tumor xenografts and lung/liver metastasis in mice. RNA pull-down, RIP (RNA immunoprecipitation), luciferase reporter assay, FISH (fluorescence in situ hybridization) and rescue experiments were used for determining the correlation among hsa_circ_0001666, miR-576-5p and PCDH10. RESULTS: Hsa_circ_0001666 was downregulated in both CRC cell lines along with tumour tissues. A higher expression level of hsa_circ_0001666 indicated a better clinical prognosis in patients with CRC. Hsa_circ_0001666 knockdown significantly supported CRC cell proliferation along with invasion and inhibited cell apoptosis in vitro. Hsa_circ_0001666 knockdown accelerated the CRC growth and metastasis in vivo. Moreover, the mechanistic study showed that hsa_circ_0001666, acting as 'ceRNA' of miR-576-5p, prevented PCDH10 downregulation, as well as suppressed EMT and stemness of CRC cells, and the Wnt/ß-catenin signalling pathway. Inhibiting miR-576-5p or overexpressing PCDH10 could reverse phenotypic changes caused by knocking down of hsa_circ_0001666. CONCLUSIONS: Hsa_circ_0001666 suppresses CRC progression through the miR-576-5p/PCDH10 axis and may provide a new insight for the diagnosis and treatment of CRC.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , MicroRNAs/efeitos dos fármacos , Protocaderinas/efeitos dos fármacos , RNA Circular/farmacologia , Idoso , Proliferação de Células/genética , China , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Circular/uso terapêuticoRESUMO
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract. According to the research of circular RNAs in the CRC field, compared with linear RNAs, circular RNAs are a special type of noncoding RNA that are covalently closed circular structures, which have no 5' cap structure and 3' polyA tail and are not affected by RNA exonuclease and actinomycin D. BIOLOGICAL FUNCTIONS: Notably, circular RNAs have a high degree of stability and potential effect on gene regulation. Meanwhile, circular RNAs are involved in the sponge action of microRNAs and mediate protein translation and direct binding, alternative splicing, and histone modification. RELATIONSHIPS WITH CRC: Studies have shown that circular RNAs are related to the proliferation, invasion, recurrence, metastasis, ferroptosis, apoptosis, and chemotherapy resistance of CRC. CONCLUSIONS: This article provides a brief review based on the source, structural characteristics, mechanisms, biological functions of circular RNAs, and the relationships between CRC.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , RNA Circular/uso terapêutico , Neoplasias Colorretais/patologia , HumanosRESUMO
Diabetic nephropathy (DN), also known as diabetic kidney disease (DKD), is a drastic renal complication of type 1 and type 2 diabetes mellitus (DM). Poorly controlled DM over the years, may disrupt kidneys' blood vessels, leading to the hypertension (HTN) and DN onset. During DN, kidneys' waste filtering ability becomes disturbed. Being on a healthy lifestyle and controlling both DM and HTN are now the best proceedings to prevent or at least delay DN occurrence. Unfortunately, about one-fourth of diabetic individuals eventually experience the corresponding renal failure, and thus it is critical to discover effective diagnostic biomarkers and therapeutic strategies to combat DN. In the past few years, circular RNAs (circRNAs), as covalently closed endogenous non-coding RNAs (ncRNAs), are believed to affect DN pathogenesis in a positive manner. CircRNAs are able to impact different cellular processes and signaling pathways by targeting biological molecules or various molecular mechanisms. Still, as a key regulatory axis, circRNAs can select miRNAs as their molecular targets, in which they are considered as miRNA sponges. In this way, circRNA-induced suppression of particular miRNAs may prevent from DN progression or promotes the DN elimination. Since the expression of circRNAs has also been reported to be increased in DN-associated cells and tissues, they can be employed as either diagnostic biomarkers or therapeutic targets.
Assuntos
Nefropatias Diabéticas/genética , Nefropatias Diabéticas/terapia , Rim/metabolismo , MicroRNAs/genética , RNA Circular/genética , Animais , Biomarcadores/metabolismo , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/metabolismo , Regulação da Expressão Gênica , Terapia Genética , Humanos , Rim/patologia , MicroRNAs/metabolismo , Valor Preditivo dos Testes , RNA Circular/metabolismo , RNA Circular/uso terapêutico , Transdução de SinaisRESUMO
BACKGROUND: Invasive Trichosporon asahii (T. asahii) infection frequently occurs with a high mortality in immunodeficient hosts, but the pathogenesis of T. asahii infection remains elusive. Circular RNAs (circRNAs) are a type of endogenous noncoding RNA that participate in various disease processes. However, the mechanism of circRNAs in T. asahii infection remains completely unknown. METHODS: RNA sequencing (RNA-seq) was performed to analyze the expression profiles of circRNAs, microRNAs (miRNAs), and mRNAs in THP-1 cells infected with T. asahii or uninfected samples. Some of the RNA-seq results were verified by RT-qPCR. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to analyze the differentially expressed mRNAs. A circRNA-miRNA-mRNA network was constructed and verified by dual-luciferase reporter assay and overexpression experiments. RESULTS: A total of 46 circRNAs, 412 mRNAs and 47 miRNAs were differentially expressed at 12 h after T. asahii infection. GO and KEGG analyses showed that the differentially expressed mRNAs were primarily linked to the leukocyte migration involved in the inflammatory response, the Toll-like receptor signaling pathway, and the TNF signaling pathway. A competing endogenous RNA (ceRNA) network was constructed with 5 differentially expressed circRNAs, 5 differentially expressed miRNAs and 42 differentially expressed mRNAs. Among them, hsa_circ_0065336 was found to indirectly regulate PTPN11 expression by sponging miR-505-3p. CONCLUSIONS: These data revealed a comprehensive circRNA-associated ceRNA network during T. asahii infection, thus providing new insights into the pathogenesis of the T. asahii-host interactions.
Assuntos
Basidiomycota/efeitos dos fármacos , MicroRNAs/farmacologia , RNA Circular/farmacologia , RNA Mensageiro/farmacologia , Tricosporonose/terapia , Basidiomycota/patogenicidade , Humanos , MicroRNAs/uso terapêutico , RNA Circular/uso terapêutico , RNA Mensageiro/uso terapêutico , Transdução de Sinais/efeitos dos fármacosRESUMO
Noncoding ribonucleic acids (ncRNAs) are an increasingly studied class of RNA molecules with extensive biological activities, including important roles in human development, health, and disease. Glaucoma is a neurodegenerative disease of the retina, and one of the leading causes of blindness worldwide. However, the specific roles of ncRNAs in the development and progression of glaucoma are unclear, and related reports are fragmented. An in-depth understanding of ncRNAs participating in the pathogenesis and progression of glaucoma would be helpful for opening up new avenues to facilitate the early diagnosis and clinical treatment. Therefore, in this review, we aimed to discuss the current research progress, the potentialfuture clinical applications and the research limitations of three critical classes of ncRNAs in glaucoma, namely microRNAs, long noncoding RNAs, and circular RNAs.
Assuntos
Glaucoma/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA Longo não Codificante/metabolismo , Retina/metabolismo , Animais , Biomarcadores/metabolismo , Diagnóstico Precoce , Regulação da Expressão Gênica , Glaucoma/diagnóstico , Glaucoma/genética , Glaucoma/terapia , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Valor Preditivo dos Testes , Prognóstico , RNA Circular/genética , RNA Circular/uso terapêutico , RNA Longo não Codificante/genética , RNA Longo não Codificante/uso terapêutico , Retina/patologiaRESUMO
Emerging evidence suggests that dysregulated circular RNAs (circRNAs) play a pivotal role in osteoarthritis (OA). Circ_0045714 is a functional circRNAs, and has been revealed to involve in the process of OA. However, the molecular mechanisms by which circ_0045714 regulates OA progression are not thoroughly elucidated. Circ_0045714 expression was decreased in OA and TNF-α-induced chondrocytes, ectopic overexpression of circ_0045714 abolished TNF-α-induced cell apoptosis, inflammation, extracellular matrix (ECM) degradation promotion and proliferation inhibition. In a mechanical study, circ_0045714 targeted miR-218-5p, and miR-218-5p overexpression reversed the effects of circ_0045714 on TNF-α-induced chondrocytes. Besides that, HRAS was a target of miR-218-5p, and HRAS knockdown attenuated the protective effects of miR-218-5p inhibition on TNF-α-induced chondrocyte dysfunction. Additionally, circ_0045714 could regulate HRAS expression via miR-218-5p in chondrocytes. Up-regulation of circ_0045714 suppressed TNF-α-induced chondrocyte growth inhibition, inflammation, and ECM degradation via miR-218-5p/HRAS axis, suggesting a novel insight into the pathogenesis of OA and the potential protective role of circ_0045714 in the occurrence and development of OA.
Assuntos
Condrócitos/efeitos dos fármacos , Matriz Extracelular/metabolismo , MicroRNAs/metabolismo , RNA Circular/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Células Cultivadas , Humanos , RNA Circular/farmacologia , TransfecçãoRESUMO
BACKGROUND: Circular RNAs (circRNAs) act as vital regulators of gene expression in a variety of cancers. However, the role of circRNAs in gastric cancer (GC) remains largely unexplored. Herein, we identified that circTMEM87A sponges miR-142-5p to promote GC progression through up-regulating ULK1 expression. METHODS: The expression of circTMEM87A in GC was determined by RNA sequencing and quantitative real-time PCR (qRT-PCR). The effects of knockdown or exogenous expression of circTMEM87A on GC cell phenotypes were evaluated both in vitro and in vivo. The interacting miRNA of circTMEM87A was predicted by bioinformatics and confirmed by RNA pull-down, dual-luciferase reporter assay and fluorescence in situ hybridization (FISH). The mechanism by which circTMEM87A/miR-142-5p/ULK1 axis promotes GC was determined by western blot, GFP/mRFP-LC3 puncta analysis, transmission electron microscope (TEM). RESULTS: CircTMEM87A was dramatically elevated in GC tissues and cell lines, and high circTMEM87A expression was closely correlated with poor prognosis of GC patients. Knockdown of circTMEM87A suppressed cell growth, migration, invasion and induced apoptosis in vitro, as well as inhibited GC tumorigenicity and lung metastasis potential in vivo. Meanwhile, circTMEM87A overexpression had the opposite effects. Furthermore, we demonstrated that circTMEM87A could act as a sponge of miR-142-5p to regulate ULK1 expression and GC progression. CONCLUSIONS: Our findings suggest that circTMEM87A functions as an oncogene through the miR-142-5p/ULK1 axis in GC. CircTMEM87A might be a prognostic biomarker as well as a promising therapeutic target for GC.
Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , MicroRNAs/efeitos dos fármacos , RNA Circular/farmacologia , Neoplasias Gástricas/etiologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/análise , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/análise , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/análise , MicroRNAs/genética , RNA Circular/uso terapêutico , Neoplasias Gástricas/fisiopatologiaRESUMO
Polycystic ovary syndrome (PCOS), the most common female endocrine disease that causes anovulatory infertility, still lacks promising strategy for the accurate diagnosis and effective therapeutics of PCOS attributed to its unclear aetiology. In this study, we determined the abnormal reduction in circPSMC3 expression by comparing the ovarian tissue samples of PCOS patients and normal individuals. The symptom relief caused by up-regulation of circPSMC3 in PCOS model mice suggested the potential for further study. In vitro functional experiments confirmed that circPSMC3 can inhibit cell proliferation and promote apoptosis by blocking the cell cycle in human-like granular tumour cell lines. Mechanism study revealed that circPSMC3 may play its role through sponging miR-296-3p to regulate PTEN expression. Collectively, we preliminarily characterized the role and possible insights of circPSMC3/miR-296-3p/PTEN axis in the proliferation and apoptosis of KGN cells. We hope that this work provides some original and valuable information for the research of circRNAs in PCOS, not only to better understand the pathogenesis but also to help provide new clues for seeking for the future therapeutic target of PCOS.