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1.
Sci Rep ; 12(1): 6625, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35459923

RESUMO

Alzheimer's disease (AD) is the most common cause of progressive dementia. In the present study, we showed hippocampal tissue transcriptome analysis in APPswe/PSEN1dE9 (APP/PS1, AD model) mice treated with fasudil (ADF) and compared with AD mice treated with saline (ADNS) and wild type mice (WT). The competing endogenous RNA (ceRNA) network was constructed and validated the differential expression of mRNA, lncRNA, miRNA, and circRNA. Our study showed differentially expressed mRNAs (DEMs) between WT and ADNS, while enriched in cell growth and death and nervous system pathways. DEMs between ADNS-ADF were enriched in the nervous system, glycosaminoglycan biosynthesis-keratan sulfate (KS) and Quorum sensing pathways. We validated four genes with RT-PCR, whereas enrichment of Acyl-CoA Synthetase Long Chain Family Member 4 (Acsl4, ENSMUST00000112903) in Quorum sensing pathways, and BTG anti-proliferation factor 1 (Btg1, ENSMUST00000038377) in RNA degradation pathways were conducted. Expression of these two genes were higher in ADNS, but were significantly reduced in ADF. Histone H4 transcription factor (Hinfp, ENSMUST00000216508) orchestrate G1/S transition of mitotic cell cycle and co-expressed with mmu-miR-26a-2-3p-mediated ceRNA and mmu-miR-3065-5p-mediated ceRNA; Wnt family member 4 (Wnt4, ENSMUST00000045747) was enriched in mTOR, Hippo and Wnt signaling pathway. Expression of these two genes were significantly lower in ADNS, and fasudil treatment reverse it. The present studies demonstrated four genes: Acsl4, Btg1, Hinfp, Wnt4 could be potential biomarkers of AD and the targets of fasudil treatment. These results will pave a novel direction for future clinic studies for AD and fasudil treatment.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina , Doença de Alzheimer , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Longo não Codificante/genética , Transcriptoma
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(3): 367-374, 2022 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-35426800

RESUMO

OBJECTIVE: To investigate the effect of triptolide (TPL) on inflammatory response and migration of fibroblast like synovial cells (FLS) in rheumatoid arthritis (RA-FLS) and the mechanism of circular noncoding RNA (circRNA) 0003353 for mediating this effect. METHODS: We collected peripheral blood mononuclear cells (PBMCs) and serum samples from 50 hospitalized RA patients and 30 healthy individuals for detecting the expression of circRNA 0003353, immune and inflammatory indexes (ESR, CRP, RF, anti-CCP, IgA, IgG, IgM, C3, and C4) and DAS28 score. Cultured RA-FLS was treated with 10 ng/mL TPL and transfected with a circRNA 0003353 overexpression plasmid, and cell counting kit-8 (CCK-8) assay and Transwell assay were used to detect the changes in the viability and migration of the cells. Enzyme-linked immunosorbent assay (ELISA) was used to examine the cytokines IL-4, IL-6, and IL-17, and real-time fluorescence quantitative PCR (RT-qPCR) was performed to detect the expression of circRNA 003353; Western blotting was used to detect the expressions of p-JAK2, pSTAT3, JAK2 and STAT3 proteins in the treated cells. RESULTS: The expression of circRNA 0003353 was significantly increased in PBMCs from RA patients and showed a good performance in assisting the diagnosis of RA (AUC=90.5%, P < 0.001, 95% CI: 0.83-0.98). CircRNA 0003353 expression was positively correlated with ESR, RF and DAS28 (P < 0.05). Treatment with TPL significantly decreased the expression of circRNA 0003353, suppressed the viability and migration ability, decreased the expressions of IL-6 and IL-17, and increased the expression IL-4 in cultured RA-FLS in a time-dependent manner (P < 0.01). TNF-α stimulation of RA-FLS significantly increased the ratios of p-JAK2/JAK2 and p-STAT3/STAT3, which were obviously lowered by TPL treatment (P < 0.01). TPL-treated RA-FLS overexpressing circRNA 0003353 showed significantly increased cell viability and migration ability with decreased IL-4 expression and increased IL-6 and IL-17 expressions and ratios of p-JAK2/ JAK2 and p-STAT3/STAT3 (P < 0.01). CONCLUSION: The expression of circRNA 0003353 is increased in PBMCs in RA patients and in RA-FLS. TPL treatment can regulate JAK2/STAT3 signal pathway and inhibit the inflammatory response and migration of RA-FLS through circRNA 0003353.


Assuntos
Artrite Reumatoide , Diterpenos , Compostos de Epóxi , Interleucina-17 , Janus Quinase 2 , Fenantrenos , RNA Circular , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Células Cultivadas , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Leucócitos Mononucleares/metabolismo , Fenantrenos/farmacologia , RNA Circular/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
3.
Viruses ; 14(4)2022 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-35458413

RESUMO

Since the onset of the HIV-1/AIDS epidemic in 1981, 75 million people have been infected with the virus, and the disease remains a public health crisis worldwide. Circular RNAs (circRNAs) are derived from excised exons and introns during backsplicing, a form of alternative splicing. The relevance of unconventional, non-capped, and non-poly(A) transcripts to transcriptomics studies remains to be routinely investigated. Knowledge gaps to be filled are the interface between host-encoded circRNAs and viral replication in chronically progressed patients and upon treatment with antiviral drugs. We implemented a bioinformatic pipeline and repurpose publicly archived RNA sequence reads from the blood of 19 HIV-1-positive patients that previously compared transcriptomes during viremia and viremia suppression by antiretroviral therapy (ART). The in silico analysis identified viremic patients' circRNA that became undetectable after ART. The circRNAs originated from a subset of host genes enriched in the HDAC biological pathway. These circRNAs and parental mRNAs held in common a small collection of miRNA response elements (MREs), some of which were present in HIV-1 mRNAs. The function of the MRE-containing target mRNA enriched the RNA polymerase II GO pathway. To visualize the interplay between individual circRNA-miRNA-target mRNA, important for HIV-1 and potentially other diseases, an Interactive Circos tool was developed to efficiently parse the intricately competing endogenous network of circRNA-miRNA-mRNA interactions originating from seven circRNA singled out in viremic versus non-viremic patients. The combined downregulation of the identified circRNAs warrants investigation as a novel antiviral targeting strategy.


Assuntos
Infecções por HIV , HIV-1 , MicroRNAs , RNA Circular , Viremia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV , HIV-1/genética , HIV-1/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA/genética , RNA Circular/genética , RNA Circular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Viremia/genética , Viremia/metabolismo
4.
Hematology ; 27(1): 431-440, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35413218

RESUMO

BACKGROUND: : Acute myeloid leukemia (AML) is regarded as a haematological malignancy and seriously threatens the public's health. Circular RNA (circRNA) is gradually confirmed to be involved in the development of AML. The purpose of this study was to disclose the role of circRNA Potassium Voltage-Gated Channel Subfamily Q Member 5 (circ_KCNQ5) in AML. METHODS: : Quantitative real-time PCR (qPCR) and western blot were used for expression analysis. Colony formation assay, EdU assay and MTT assay were performed to determine cell proliferation. Flow cytometry assay was conducted to determine cell apoptosis. The predicted binding relationship between miR-622 and circ_KCNQ5 or RAS oncogene family member 10 (RAB10) was verified by dual-luciferase reporter assay. RESULTS: : The expression of circ_KCNQ5 was increased in bone marrow samples of childhood AML patients and AML cell lines. The knockdown of circ_KCNQ5 largely suppressed AML cell proliferation and promoted cell apoptosis. Circ_KCNQ5 directly bound to miR-622 and inhibited miR-622 expression. The cotransfection of miR-622 inhibitor reversed the effects of circ_KCNQ5 knockdown and thus recovered cell proliferation and depleted cell apoptosis. RAB10 was a target of miR-622, and circ_KCNQ5 bound to miR-622 to increase the expression of RAB10. MiR-622 restoration inhibited AML cell proliferation and induced cell apoptosis, while RAB10 overexpression abolished these effects. CONCLUSION: : Circ_KCNQ5 high expression was associated with childhood AML malignant development, and circ_KCNQ5 participated in AML progression by regulating the miR-622/RAB10 pathway.


Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Transtornos Mieloproliferativos , RNA Circular , Apoptose , Proliferação de Células/genética , Criança , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
5.
J Orthop Surg Res ; 17(1): 159, 2022 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-35279159

RESUMO

BACKGROUND: Studies of aberrantly expressed circular RNAs (circRNAs) can provide insights into the molecular mechanisms of osteosarcoma (OS). However, the role of circ_0001174 in OS progression remains unknown. This study is aimed to identify differentially expressed circRNAs and messenger RNAs (mRNAs) in patients with OS and to investigate potential regulatory ways of circ_0001174. METHODS: High-throughput sequencing was performed to screen aberrantly expressed circRNAs and mRNAs between tumor and paracancerous tissues from patients with OS. Several bioinformatics tools were used to analyze the functions and pathways of the differentially expressed genes between the tissues. Cell counting kit-8, cell migration and invasion assays were performed to evaluate the functions of the critical circRNAs. RNA interference experiments, quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting were used to explore the relationship between miR-186-5p and circ_0001174 or metastasis-associated in colon cancer 1 (MACC1). RESULTS: Compared with the paracancerous tissues, 109 circRNAs and 1264 mRNAs were differentially expressed in the OS tissues, including 88 circRNAs and 707 mRNAs that were upregulated and 21 circRNAs and 557 mRNAs that were downregulated. The expression of four upregulated and four downregulated circRNAs was validated using RT-qPCR; the results were consistent with the sequencing data, and circ_0001174 was found to be significantly upregulated in 16 pairs of OS tissues and OS cell lines (fold change > 2.0, P value < 0.05). Knockdown of circ_0001174 inhibited the proliferation, migration, and invasion of OS cells. Additionally, circ_0001174 directly and negatively modulated the expression of miR-186-5p and positively regulated the expression of MACC1. CONCLUSIONS: Abnormally high expression of circ_0001174 may promote the proliferation, migration, and invasion of OS cells through up-regulating MACC1 by sponging miR-186-5p. These results provide insight into therapeutic targets for preventing and treating OS.


Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Proliferação de Células/genética , MicroRNAs/genética , Osteossarcoma/genética , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Reação em Cadeia da Polimerase em Tempo Real , Transativadores
6.
Bioengineered ; 13(2): 3651-3664, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35230201

RESUMO

In recent years, the problem of cancer resistance has become more and more prominent, seriously affecting treatment efficiency. Circular RNAs (circRNAs) play an important role in cell progression and cancer mechanisms. However, there is a lack of systematic studies on its function in non-small cell lung cancer (NSCLC) resistance. CircPTK2, microRNA-942 (miR-942), and Tripartite motif 16 (TRIM16) levels were detected by Real-time quantitative reverse transcriptase PCR (qRT-PCR). Extracellular acidification rate (ECAR), glucose consumption, and lactate production were assessed using the Seahorse XF96 Glycolysis Analyzer, glucose, and lactate assay kits, respectively. The protein expression was measured with the western bolt Transwell assay was used to determine migration and invasion of transfected cells. (4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry were applied to carry out cell proliferation and apoptosis, respectively. The relationship among circPTK2, miR-942, and TRIM16 were determined by using the dual-luciferase reporter assay and RIP assay. circPTK2 (hsa_circ_0008305) and TRIM16 were low expressed, while miR-942 was significantly highly expressed in NSCLC tissues and cell lines. Moreover, overexpression of circPTK2 remarkably inhibited cell growth, metastasis, and glycolysis in A549/CDDP and H1299/CDDP cells. Promotion of miR-942 or inhibition of TRIM16 could reverse the effects of high circPTK2 expression on cell growth, metastasis, and glycolysis in A549/CDDP and H1299/CDDP cells. CircPTK2 overexpression inhibited the growth of A549/CDDP cells in vivo. Furthermore, circPTK2 weakened CDDP resistance of NSCLC through modulating miR-942/TRIM16 axis, providing a novel sight for the treatment of NSCLC and improving the understanding of the CDDP resistance mechanism of NSCLC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Quinase 1 de Adesão Focal/genética , MicroRNAs/genética , RNA Circular/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Células A549 , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Feminino , Quinase 1 de Adesão Focal/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/metabolismo , RNA Circular/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
BMC Cancer ; 22(1): 265, 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35287604

RESUMO

BACKGROUND: Reportedly, circular RNA (circRNA) is a key modulator in the development of human malignancies. This work is aimed to probe the expression pattern, biological effects and mechanism of circ_0064288 on hepatocellular carcinoma (HCC) progression. METHODS: The differentially expressed circRNA was screened by analyzing the expression profiles of circRNAs in HCC tissues and normal tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine the expression of circ_0064288, miR-335-5p and Rho associated coiled-coil containing protein kinase 1 (ROCK1) mRNA in HCC specimens. After circ_0064288 was overexpressed or knocked down in HCC cells, cell growth was detected by the CCK-8 experiment, and cell migration was evaluated using Transwell experiment and scratch healing experiment. The targeting relationship between miR-335-5p and circ_0064288 and ROCK1 mRNA was predicted and verified using bioinformatic analysis and dual-luciferase reporter gene experiments, respectively. Western blot was executed to examine ROCK1 protein expression in HCC cells. RESULTS: Circ_0064288 and ROCK1 expression was up-modulated in HCC, while miR-335-5p was down-modulated. High circ_0064288 expression was associated with shorter survival time of HCC patients. It was also revealed that circ_0064288 overexpression remarkably enhanced HCC cell growth and migration, while knockdown of circ_0064288 induced opposite effects. Additionally, circ_0064288 could competitively bind with miR-335-5p thereby up-modulate ROCK1 expression. MiR-335-5p overexpression partly counteracted the effect of circ_0064288 overexpression on HCC cells. CONCLUSION: Circ_0064288 facilitates HCC cell growth and migration by modulating the miR-335-5p/ROCK1 axis.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , Quinases Associadas a rho/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Oncogenes/genética , Reação em Cadeia da Polimerase em Tempo Real
8.
J Biol Chem ; 298(4): 101828, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35305988

RESUMO

Neural stem cells (NSCs) persist in the dentate gyrus of the hippocampus into adulthood and are essential for both neurogenesis and neural circuit integration. Exosomes have also been shown to play vital roles in regulating biological processes of receptor cells as a medium for cell-to-cell communication signaling molecules. The precise molecular mechanisms of exosome-mediated signaling, however, remain largely unknown. Here, we found that exosomes produced by denervated hippocampi following fimbria-fornix transection could promote the differentiation of hippocampal neural precursor cells into cholinergic neurons in coculture with NSCs. Furthermore, we found that 14 circular RNAs (circRNAs) were upregulated in hippocampal exosomes after fimbria-fornix transection using high-throughput RNA-Seq technology. We further characterized the function and mechanism by which the upregulated circRNA Acbd6 (acyl-CoA-binding domain-containing 6) promoted the differentiation of NSCs into cholinergic neurons using RT-quantitative PCR, Western blot, ELISA, flow cytometry, immunohistochemistry, and immunofluorescence assay. By luciferase reporter assay, we demonstrated that circAcbd6 functioned as an endogenous miR-320-5p sponge to inhibit miR-320-5p activity, resulting in increased oxysterol-binding protein-related protein 2 expression with subsequent facilitation of NSC differentiation. Taken together, our results suggest that circAcbd6 promotes differentiation of NSCs into cholinergic neurons via miR-320-5p/oxysterol-binding protein-related protein 2 axis, which contribute important insights to our understanding of how circRNAs regulate neurogenesis.


Assuntos
Diferenciação Celular , Neurônios Colinérgicos , MicroRNAs , Células-Tronco Neurais , RNA Circular , Receptores de Esteroides , Animais , Diferenciação Celular/genética , Neurônios Colinérgicos/citologia , MicroRNAs/genética , MicroRNAs/metabolismo , Células-Tronco Neurais/citologia , RNA Circular/genética , RNA Circular/metabolismo , Ratos , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo
9.
BMC Endocr Disord ; 22(1): 67, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35291991

RESUMO

BACKGROUND: Circular RNA (circRNA) has been shown to mediate diabetic nephropathy (DN) development by regulating renal tubular epithelial cells (RTECs) injury. However, the role and mechanism of circ_0000064 in high glucose (HG)-induced RTECs injury have not been fully elucidated. METHODS: Human RTECs (HK-2) were exposed to HG to induce cell injury. Cell oxidative stress was assessed by detecting the levels of oxidative stress-markers. Moreover, cell proliferation and apoptosis were determined by CCK8 assay, EDU assay and flow cytometry. The protein levels of proliferation markers, apoptosis markers and Rho-associated coiled-coil-containing kinase 1 (ROCK1) were measured using western blot analysis. Furthermore, quantitative real-time PCR was performed to assess the expression of circ_0000064, microRNA (miR)-532-3p and ROCK1. The interaction between miR-532-3p and circ_0000064 or ROCK1 was confirmed by dual-luciferase reporter assay and RNA pull-down assay. RESULTS: Our results revealed that HG treatment could promote HK-2 cells oxidative stress, apoptosis, fibrosis, and inhibit proliferation. Circ_0000064 expression was increased in the serum of DN patients and HG-induced HK-2 cells, and silenced circ_0000064 could relieve HG-induced HK-2 cells injury. MiR-532-3p could be sponged by circ_0000064, and its overexpression also alleviated HG-induced HK-2 cells injury. Besides, the regulation of circ_0000064 knockdown on HG-induced HK-2 cells injury could be reversed by miR-532-3p inhibitor. Additionally, ROCK1 was a target of miR-532-3p, and its expression was inhibited by circ_0000064 knockdown. The inhibition effect of circ_0000064 knockdown on HG-induced HK-2 cells injury also could be reversed by overexpressing ROCK1. CONCLUSION: In summary, circ_0000064 knockdown might alleviate HG-induced HK-2 cells injury via regulating the miR-532-3p/ROCK1 axis, which provided a new perspective for DN treatment.


Assuntos
Nefropatias Diabéticas/metabolismo , Células Epiteliais/metabolismo , Túbulos Renais/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Quinases Associadas a rho/metabolismo , Progressão da Doença , Glucose/farmacologia , Humanos
10.
Int J Oncol ; 60(4)2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35211755

RESUMO

Circular RNA­lipoprotein receptor 6 (circ­LRP6) serves a role in promoting the tumorigenesis of retinoblastoma, esophageal squamous cell cancer and oral squamous cell carcinoma; however, whether circ­LRP6 demonstrates the same effect in osteosarcoma (OS) is yet to be fully elucidated. The present study aimed to analyze the expression, role and potential molecular mechanism of circ­LRP6 in OS. The expression levels of circ­LRP6, microRNA (miR)­141­3p, histone deacetylase 4 (HDAC4) and high mobility group protein 1 (HMGB1) were evaluated by reverse transcription-quantitative PCR in OS tissues and cell lines. Cell Counting Kit­8, Transwell and Matrigel assays were conducted to evaluate cell proliferation, migration and invasion, respectively. Western blotting was also performed to determine HDAC4 and HMGB1 protein expression levels. Bioinformatics and dual­luciferase reporter assays were used to predict and analyze the interactions between circ­LRP6 and miR­141­3p, miR­141­3p and HDAC4, as well as between miR­141­3p and HMGB1. Additionally, RNA immunoprecipitation was performed to verify the association between circ­LRP6 and miR­141­3p. The results confirmed that circ­LRP6 was highly expressed in OS tissues and cell lines. In addition, circ­LRP6 negatively regulated the expression of miR­141­3p and, in turn, miR­141­3p negatively regulated HDAC4 and HMGB1 expression. Functional assays revealed that circ­LRP6 knockdown inhibited the proliferation, migration and invasion of OS cells, whereas the inhibition of miR­141­3p or the overexpression of either HDAC4 or HMGB1 partly reversed the inhibitory effect of circ­LRP6 knockdown. In summary, the present study determined that circ­LRP6 knockdown inhibited the proliferation, migration and invasion of OS cells by regulating the miR­141­3p/HDAC4/HMGB1 axis.


Assuntos
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Osteossarcoma/metabolismo , Adolescente , Adulto , Criança , Feminino , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Osteossarcoma/fisiopatologia , RNA Circular/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
11.
Bioengineered ; 13(2): 4411-4427, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35114890

RESUMO

Circular RNA circ_UBAP2 has been reported to be closely associated with various tumors. The present work focused on exploring the roles of circ_UBAP2 and its molecular mechanism in osteosarcoma (OS). Circ_UBAP2, miR-637, and high-mobility group box (HMGB) 2 levels in OS cells and tissues were detected by quantitative real-time polymerase chain reaction. The relationship between miR-637 and circ_UBAP2, as well as between miR-637 and HMGB2, was predicted and examined through bioinformatics analysis and luciferase reporter gene experiments. Moreover, OS cell growth, invasion, migration, and apoptosis were detected using the cell counting kit-8 (CCK-8), Transwell and flow cytometry assays, respectively. HMGB2 protein levels were measured using Western blotting. Xenograft tumor formation assay was also performed. Circ_UBAP2 showed high expression levels in OS tissues and cells, which was directly proportional to metastasis and clinical stage of OS. The overexpression of circ_UBAP2 enhanced the growth, invasion, and migration of OS cells, but suppressed their apoptosis. In contrast, circ_UBAP2 silencing had opposite effects. Furthermore, miR-637 served as a downstream target of circ_UBAP2, which played opposite roles to circ_UBAP2 in OS. More importantly, HMGB2 served as miR-637's downstream target. The xenograft experiments in nude mice also proved that knockdown of circ_UBAP2 could increase miR-637 expression, but decrease HMGB2 expression, thus alleviating OS progression. Mechanistically, circ_UBAP2 exerts a cancer-promoting effect on OS by downregulating miR-637 and upregulating the expression of HMGB2. Circ_UBAP2 plays a promoting role in OS, and the circ_UBAP2/miR-637/HMGB2 axis is involved in OS progression.


Assuntos
Neoplasias Ósseas , Proteína HMGB2/genética , MicroRNAs/genética , Osteossarcoma , RNA Circular/genética , Adolescente , Adulto , Animais , Apoptose/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Osso e Ossos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Proteína HMGB2/metabolismo , Humanos , Masculino , Camundongos , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , RNA Circular/metabolismo , Adulto Jovem
12.
Ann Clin Lab Sci ; 52(1): 48-59, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35181618

RESUMO

OBJECTIVE: Osteoporosis is likely becoming a new disease challenge with increasing aging population. Circ_0006873 dysregulation may serve as an event linked to osteoporosis. Thus, this study sought to evaluate the function and mechanism of circ_0006873 on osteoporosis. METHODS: Clinical serum samples collected from 30 osteoporosis patients were utilized to obtain circ_0006873 and miR-142-5p expression data. The link between circ_0006873, miR-142-5p, and phosphatase and tensin homolog (PTEN) was demonstrated via online tools (starBase, circinteractome), RNA Immunoprecipitation (RIP) and dual-Luciferase reporter assays. After knockdown or overexpression, cell counting kit-8 (CCK-8) assay measured cell viability. Alizarin red S (ARS) staining as well Alkaline phosphatase (ALP) staining detected osteoblastic differentiation levels. Quantitative real-time PCR (qRT-PCR) and western blot analyzed expression of RNAs and proteins after transfection or during osteoblastic differentiation. RESULTS: circ_0006873 was upregulated in osteoporosis patients and decreased during osteoblastic differentiation. Following experiments revealed that cell viability, proliferation-related factors, osteogenic marker genes (ALP, Runx2, Bglap) and osteoblastic differentiation degree were promoted after circ_0006873 knockdown but inhibited after overexpression. Circ_0006873 sponged miR-142-5p, which was downregulated in osteoporosis patients and became higher during osteoblastic differentiation. Rescue assay indicated miR-142-5p mimic could reverse the effects of circ_0006873 overexpression on cell viability and osteogenic markers, and also could activate Akt pathway. Furthermore, circ_0006873 can negatively target miR-142-5p via regulating PTEN to inhibit osteoblastic differentiation. CONCLUSION: Circ_0006873 sponges miR-142-5p thereby enhances PTEN expression to suppress osteoblastic differentiation via regulation of Akt signaling pathway, thus, may provide a treatment approach for osteoporosis.


Assuntos
Células-Tronco Mesenquimais , MicroRNAs , Osteoblastos , Osteoporose , PTEN Fosfo-Hidrolase , Proteínas Proto-Oncogênicas c-akt , RNA Circular , Idoso , Diferenciação Celular , Humanos , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoporose/sangue , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Transdução de Sinais
13.
Ann Clin Lab Sci ; 52(1): 109-116, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35181624

RESUMO

OBJECTIVE: To investigate the function and mechanism of circular RNA circ HIPK2 on non-small cell lung cancer cell proliferation and progression. METHODS: Patients with non-small cell lung cancer (n=40) were collected from May 2015 to August 2016. RESULTS: Circular RNA circ HIPK2 expressions were up-regulated in patients with non-small cell lung cancer, compared with paracancerous tissue. Circular RNA circ HIPK2 expressions in III-IV patients with non-small cell lung cancer were higher than those of I-II patients. Overall survival rate and disease-free survival rate of patients with high circ HIPK2 expression were lower than those of patients with low circ HIPK2 expression. Circ HIPK2 promoted cell proliferation of non-small cell lung cancer. MiR-485-5p is a target for circ HIPK2 in non-small cell lung cancer; it reduced cell proliferation and accelerated HSP90 Ubiquitination in non-small cell lung cancer. CONCLUSION: The present study suggests that circ HIPK2/miR-485-5p plays a crucial role in the progression of non-small cell lung cancer by regulating HSP90 function, thereby may be an inhibition therapeutic target of non-small cell lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Proteínas de Choque Térmico HSP90 , Neoplasias Pulmonares , MicroRNAs , RNA Circular , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proliferação de Células/genética , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Ubiquitinação
14.
Mol Cancer ; 21(1): 49, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35164758

RESUMO

BACKGROUND: Exosomes have emerged as vital biomarkers of multiple cancers and contain abundant circular RNAs (circRNAs). However, the potential for exosomal circRNAs to be used in diagnostics and their molecular mechanism of action in colorectal cancer (CRC) remain unclear. METHODS: CRC-specific exosomal circRNAs were identified by RNA sequencing, exoRBase database and a tissue microarray. The diagnostic performance of plasma exosomal circRNAs was evaluated among cancer-free controls, precancer individuals, CRC patients, and patients with other types of cancer. The corresponding biological functions were mainly assessed using circRNA pull-down, proteomic analysis, and RNA immunoprecipitation assay underlying cellular and mouse models. RESULTS: CircLPAR1 was encapsulated in exosomes with high stability and detectability, and its expression in plasma exosomes was remarkably decreased during CRC development but recovered after surgery. Exosomal circLPAR1 showed cancer specificity in CRC diagnosis and increased the diagnostic performance to an area under the receiver operating characteristic curve of 0.875, as determined by analysing its performance in combination with common clinical biomarkers CEA and CA19-9. Additionally, circLPAR1 was downregulated in CRC tissues and was associated with overall survival. Mechanistically, exosomal circLPAR1 was internalized by CRC cells, and it suppressed tumor growth, likely because exosomal circLPAR1 directly bound with eIF3h specifically suppressed the METTL3-eIF3h interaction, decreasing the translation of oncogene BRD4. CONCLUSIONS: This comprehensive study highlights plasma exosomal circLPAR1 as a promising predictor in CRC diagnosis and describes its biological regulation of colorectal tumorigenesis. This study provides a new perspective on early diagnosis in the clinic and pathogenesis in disease development.


Assuntos
Proteínas de Ciclo Celular , Neoplasias Colorretais , Exossomos , Metiltransferases , RNA Circular , Fatores de Transcrição , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Exossomos/metabolismo , Humanos , Metiltransferases/metabolismo , Camundongos , Proteínas Nucleares/metabolismo , Proteômica , RNA Circular/genética , RNA Circular/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
Mol Cancer ; 21(1): 51, 2022 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-35164771

RESUMO

BACKGROUND: N6-methyladenosine (m6A) RNA methylation and circular RNAs (circRNAs) have been shown to act vital roles in multiple malignancies including gastric cancer (GC). However, there is little knowledge about how m6A modification of circRNAs contributes to GC progression. METHODS: The association of METTL14 expression with the clinicopathological characteristics and prognosis in patients with GC was assessed by Western blot, Immunohistochemistry and public datasets. In vitro and vivo function experiments were conducted to investigate the role of METTL14 in GC. Furthermore, m6A-circRNA epitranscriptomic microarray was utilized to identify METTL14-mediated m6A modification of circRNAs, which were validated by methylated RNA immunoprecipitation (Me-RIP), RT-qPCR and rescue experiments in GC cells. The sponge of circORC5 with miR-30c-2-3p was confirmed by luciferase gene report and RNA immunoprecipitation assays. The expression, localization and prognosis of circORC5 in GC were evaluated by fluorescence in situ hybridization. The effects of METTL14 and (or) circORC5 on miR-30c-2-3p-mediated AKT1S1 and EIF4B were estimated by RT-qPCR and Western blot analyses. RESULTS: We found that METTL14 was downregulated in GC tissue samples and its low expression acted as a prognostic factor of poor survival in patients with GC. Ectopic expression of METTL14 markedly repressed growth and invasion of GC cells in vitro and in vivo, whereas knockdown of METTL14 harbored the opposite effects. Mechanically, m6A-circRNA epitranscriptomic microarray and Me-RIP identified circORC5 as the downstream target of METTL14. Silencing of METTL14 reduced the m6A level of circORC5, but increased circORC5 expression. Moreover, circORC5 could sponge miR-30c-2-3p, and reverse METTL14-caused upregulation of miR-30c-2-3p and downregulation of AKT1S1 and EIF4B. In addition, circORC5 possessed a negative correlation with miR-30c-2-3p and indicated a poor survival in GC. CONCLUSION: Our findings demonstrate that METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Metiltransferases , MicroRNAs , RNA Circular , Neoplasias Gástricas , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Metiltransferases/genética , Metiltransferases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
16.
Epigenomics ; 14(4): 199-217, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35172608

RESUMO

Aims: The authors aim to investigate the function of circPlekha7 in renal fibrosis. Methods: Human renal tissues from chronic kidney disease patients, kidney cell line and primary cultured renal tubular epithelial cells were used. TGF-ß1-treated human kidney 2 cells/tubular epithelial cells and a unilateral ureteral obstruction mouse model were employed to study renal fibrosis. Results: circPlekha7 was diminished in renal tissues from chronic kidney disease patients and TGF-ß1-treated human kidney 2 cells and tubular epithelial cells, while miR-493-3p was upregulated. Overexpression of circPlekha7 or knockdown of miR-493-3p suppressed TGF-ß1 induced enhancements on epithelial to mesenchymal transition and fibrogenesis, as well as attenuated renal fibrosis and injury in mice subjected to unilateral ureteral obstruction. circPlekha7 bound with miR-493-3p, which directly targeted KLF4. Conclusion: circPlekha7 inhibits epithelial to mesenchymal transition of renal tubular epithelial cells and fibrosis via targeting miR-493-3p to de-repress KLF4/mitofusin2 expression.


Chronic kidney disease (CKD) ultimately leads to complete kidney dysfunction. The incidence of CKD continues to rise as a result of the increasingly aging population, and the treatment is very limited. In this study, the authors identified a novel molecule, circPlekha7, that plays a crucial role in CKD development and progression. The level of circPlekha7 is lower in the kidney tissues of CKD patients, and increasing its level could attenuate kidney injury and fibrosis. This work helps researchers understand the disease better and, more importantly, provides new avenues to develop therapy.


Assuntos
MicroRNAs , RNA Circular , Insuficiência Renal Crônica , Animais , Transição Epitelial-Mesenquimal , Fibrose , Humanos , Rim/patologia , /metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Transdução de Sinais
17.
Cell Transplant ; 31: 9636897221081479, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35225027

RESUMO

Pulmonary arterial hypertension (PAH) is a disease that plagues a major portion of the world's population, and there is currently no effective cure for this ailment. The proliferation and migration of pulmonary artery smooth muscle cells (PASMC) are known to be the pathological basis of pulmonary vascular remodeling in pulmonary hypertension. Studies in the past have shown involvement of CircRNA in the pathology of pulmonary as well as cardiovascular diseases. However, there are very few studies that have analyzed the relationship between CircRNA and PAH. The aim of this study was to explore this relationship by using rat PAH model. A hypoxic, PAH rat model was constructed for this study and the subsequently produced hypoxia-induced rat PASMC cells were utilized to demonstrate the reduction in expression of circular RNA of Silent information regulator factor 2-related enzyme 1 (circ-Sirt1) and SIRT1 mRNA in response to hypoxia, through cell function tests, cell rescue tests, and physical tests. We found that the expression of circ-Sirt1 and SIRT1 decreased in the PAH rat model induced by hypoxia. It was also revealed that the overexpression of circ-SIRT1 increased SIRT1 levels, but inhibited the expression of transforming growth factor (TGF)-ß1, Smad3, and Smad7, and weakened PASMC cell vitality, proliferation, and migration ability. The findings of the present study indicate that circ-Sirt1 regulates the expression of SIRT1 mRNA and inhibits TGF-ß1/Smad3/Smad7 mediated proliferation and migration of PASMC. This provides a new insight into the molecular mechanism of pulmonary artery vascular remodeling in PAH and may aid in the development of novel therapeutic options for management of PAH.


Assuntos
Hipertensão Pulmonar , RNA Circular , Sirtuína 1 , Animais , Proliferação de Células/genética , Células Cultivadas , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipóxia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Ratos , Sirtuína 1/genética , Sirtuína 1/metabolismo , Remodelação Vascular/genética
18.
Cell Cycle ; 21(10): 1091-1102, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35220873

RESUMO

Gastric cancer (GC) is one of the most common malignant tumors. Circular RNA (circRNA) has been shown to be involved in the progression of GC. However, the function of circ_0008035 in GC has not been studied. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of circ_0008035, microRNA-1256 (miR-1256) and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6). 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, and transwell assay were used to detect cell function. Western blot examined the protein levels of Ki67, Bax, MMP-2, and CEACAM6. The relationship between miR-1256 and circ_0008035 or CEACAM6 was verified by dual-luciferase reporter assays and RNA pull down. The xenotransplantation model was established in BALB/c nude mice to study the role of circ_0008035 in vivo. Circ_0008035 and CEACAM6 were significantly high-expressed in GC tissues and cells. Silencing of circ_0008035 reduced GC cell proliferation, migration, and invasion while enhancing apoptosis. MiR-1256 was a target of circ_0008035. The inhibition effect of circ_0008035 knockdown on the malignant behavior of GC cells could be reversed by miR-1256 inhibitor. In addition, CEACAM6 was a target of miR-1256. Overexpression of CEACAM6 partially restored the inhibitory effect of miR-1256 on cell progression. Animal experiments confirmed the anti-tumor effect of circ_0008035 knockdown in vivo. Collectively, circ_0008035 regulated the expression of CEACAM6 by sponging miR-1256, thereby promoting the development of GC. Our data provided a novel targeted therapy for GC.


Assuntos
Antígenos CD , Moléculas de Adesão Celular , Proteínas Ligadas por GPI , MicroRNAs , RNA Circular , Neoplasias Gástricas , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
19.
J Clin Lab Anal ; 36(4): e24262, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35212425

RESUMO

Circular RNAs hold significant regulatory functions during various tumors. However, the exact hsa_circ_0041268 roles in non-small cell lung cancer (NSCLC) along with regulatory mechanism are unknown. In this study, RT-qPCR was used to perceive hsa_circ_0041268 expressions in NSCLC cell lines. Our team constructed small interfering RNA for hsa_circ_0041268. NSCLC cell proliferation, migration, and tumorigenesis in nude mice were assayed to confirm hsa_circ_0041268 activities in NSCLC cells. We then used bioinformatics and luciferase reporter analyses to characterize the hsa_circ_0041268 downstream targets. The result shows that the expressions of hsa_circ_0041268 incremented in NSCLC cell lines and hsa_circ_0041268 downregulation decreased cell proliferation and migration. ROCK1 and miR-214-5p were hsa_circ_0041268 downstream targets. miR-214-5p downregulation or ROCK1 overexpression restored migration and proliferation abilities after hsa_circ_0041268 silencing. ROCK1 overexpression renovated migration and proliferation abilities after miR-214-5p overexpression. In vivo investigations confirmed that hsa_circ_0041268 downregulation inhibited tumor formation and metastasis in nude mice xenografts. Together, results demonstrated that hsa_circ_0041268 acted as tumor promoter through novel hsa_circ_0041268/miR-214-5p/ROCK1 axis, which highlighted its potential as NSCLC therapeutic agent.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , RNA Circular , Quinases Associadas a rho , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Transdução de Sinais , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
20.
Int J Mol Sci ; 23(3)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35162956

RESUMO

Circular RNAs (circRNAs) are an emerging group of long non-coding RNAs (lncRNAs) and have attracted attention again according to the progress in high-throughput sequencing in recent years. circRNAs are genome transcripts produced from pre-messenger (m)RNA regions in a specific process called "back-splicing," which forms covalently closed continuous loops. Due to their lack of a 5' cap and 3' poly-adenylated tails, circRNAs are remarkably more stable than linear RNAs. Functionally, circRNAs can endogenously sponge to microRNAs, interact with RNA-binding proteins (RBPs), or translate themselves. Moreover, circRNAs can be expressed in cell type- or tissue-specific expression patterns. Therefore, they are proposed to play essential roles in fine-tuning our body's homeostasis by regulating transcription and translation processes. Indeed, there has been accumulating emergent evidence showing that dysregulation of circRNAs can lead to metabolic disorders. This study explored the current knowledge of circRNAs that regulate molecular processes associated with glucose and lipid homeostasis and related pathogeneses of metabolic disorders. We also suggest the potential role of circRNAs as disease biomarkers and therapeutic targets.


Assuntos
Doenças Metabólicas/genética , RNA Circular/genética , RNA Circular/metabolismo , Regulação da Expressão Gênica , Marcadores Genéticos , Humanos , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , Análise de Sequência de RNA
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