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1.
Immunity ; 55(8): 1386-1401.e10, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35931086

RESUMO

Deleterious somatic mutations in DNA methyltransferase 3 alpha (DNMT3A) and TET mehtylcytosine dioxygenase 2 (TET2) are associated with clonal expansion of hematopoietic cells and higher risk of cardiovascular disease (CVD). Here, we investigated roles of DNMT3A and TET2 in normal human monocyte-derived macrophages (MDM), in MDM isolated from individuals with DNMT3A or TET2 mutations, and in macrophages isolated from human atherosclerotic plaques. We found that loss of function of DNMT3A or TET2 resulted in a type I interferon response due to impaired mitochondrial DNA integrity and activation of cGAS signaling. DNMT3A and TET2 normally maintained mitochondrial DNA integrity by regulating the expression of transcription factor A mitochondria (TFAM) dependent on their interactions with RBPJ and ZNF143 at regulatory regions of the TFAM gene. These findings suggest that targeting the cGAS-type I IFN pathway may have therapeutic value in reducing risk of CVD in patients with DNMT3A or TET2 mutations.


Assuntos
Doenças Cardiovasculares , Dioxigenases , DNA Metiltransferase 3A , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/genética , Dioxigenases/metabolismo , Humanos , Interferons/metabolismo , Macrófagos/metabolismo , Mitocôndrias/genética , Mutação/genética , Nucleotidiltransferases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transativadores/metabolismo
2.
Biochem Biophys Res Commun ; 622: 170-176, 2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-35932528

RESUMO

Gene expression is tightly regulated by transcription factors (TFs) which play an important role in development and tumorigenesis. Abnormal transcriptional regulation leads to oncogene activation or tumor suppressor inhibition, thus promoting the occurrence and progression of tumors. MYBL2 (alias B-Myb), a ubiquitously expressed transcription factor of the MYB family, is a nuclear protein involved in cell cycle progression and overexpressed and associated with poor patient outcomes in numerous cancer entities. However, the further effectors of the MYBL2 downstream transcriptional network mediating its cancer-promoting properties remain not well elaborated. Here, we systemic investigated the global MYBL2 targets base on ChIP-seq data from melanoma, breast cancer, lung carcinoma, and liver cancer. Functional enrichment and further validation of MYBL2 downstream binding targets on melanoma cells demonstrated that genes in the Ras and ErbB signaling pathways were regulated by MYBL2. Moreover, when integrating breast cancer, lung carcinoma and liver cancer data, we identified HEB, ZEB1 and ASCL1 colocalized on Ras/ErbB signaling gene locus with MYBL2, indicating the regulatory complex on activating oncogenic expression. Taken together, this study provides a reference for a better understanding of the MYBL2 regulatory mechanism in tumorigenesis.


Assuntos
Neoplasias da Mama , Carcinoma , Neoplasias Hepáticas , Neoplasias Pulmonares , Melanoma , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias da Mama/genética , Carcinogênese/genética , Carcinoma/genética , Proteínas de Ciclo Celular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/genética , Melanoma/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
3.
Molecules ; 27(15)2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35956950

RESUMO

HBx plays a significant role in the cccDNA epigenetic modification regulating the hepatitis B virus (HBV) life cycle and in hepatocyte proliferation and carcinogenesis. By using the sleeping-beauty transposon system, we constructed a tetracycline-induced HBx-expressing stable cell line, SBHX21. HBx with a HiBiT tag can be quickly detected utilizing a NanoLuc-based HiBiT detection system. By screening a drug library using SBHX21 cells, we identified estradiol benzoate as a novel anti-HBx agent. Estradiol benzoate also markedly reduced the production of HBeAg, HBsAg, HBV pgRNA, and HBV DNA in a dose-dependent manner, suggesting that estradiol benzoate could be an anti-HBV agent. Docking model results revealed that estradiol benzoate binds to HBx at TRP87 and TRP107. Collectively, our results suggest that estradiol benzoate inhibits the HBx protein and HBV transcription and replication, which may serve as a novel anti-HBV molecular compound for investigating new treatment strategies for HBV infection.


Assuntos
Vírus da Hepatite B , Transativadores , Estradiol/análogos & derivados , Células Hep G2 , Vírus da Hepatite B/metabolismo , Humanos , Luciferases , Transativadores/genética , Transativadores/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Replicação Viral
4.
Cells ; 11(14)2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35883634

RESUMO

TLR4 plays a pivotal role in orchestrating inflammation and tissue repair. Its expression has finally been balanced to initiate the early, robust immune response necessary for efficient repair without excessively amplifying and prolonging inflammation, which impairs healing. Studies show Flightless I (Flii) is an immunomodulator that negatively regulates macrophage TLR4 signalling. Using macrophages from Flii+/-, WT, and FliiTg/Tg mice, we have shown that elevated Flii reduces early TLR4 surface expression, delaying and reducing subsequent TNF secretions. In contrast, reduced Flii increases surface TLR4, leading to an earlier robust TNF peak. In Flii+/- mice, TLR4 levels peak earlier during wound repair, and overall healing is accelerated. Fewer neutrophils, monocytes and macrophages are recruited to Flii+/- wounds, leading to fewer TNF-positive macrophages, alongside an early peak and a robust shift to M2 anti-inflammatory, reparative Ym1+ and IL-10+ macrophages. Importantly, in diabetic mice, high Flii levels are found in plasma and unwounded skin, with further increases observed in their wounds, which have impaired healing. Lowering Flii in diabetic mice results in an earlier shift to M2 macrophages and improved healing. Overall, this suggests Flii regulation of TLR4 reduces early inflammation and decreases the M2 macrophage phenotype, leading to impaired healing.


Assuntos
Proteínas dos Microfilamentos , Receptor 4 Toll-Like , Transativadores , Cicatrização , Animais , Diabetes Mellitus Experimental , Inflamação/genética , Inflamação/metabolismo , Macrófagos/metabolismo , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Receptor 4 Toll-Like/metabolismo , Transativadores/genética , Transativadores/metabolismo , Cicatrização/genética , Cicatrização/fisiologia
5.
Ann Clin Lab Sci ; 52(3): 439-451, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35777798

RESUMO

OBJECTIVE: Cancer stem-like cells (CSLCs) are closely associated with tumor recurrence, metastasis, and drug-resistance. PHD-finger domain protein 5A (PHF5A) is related to tumorigenesis and development of non-small cell lung cancer (NSCLC). The role and regulatory mechanism of PHF5A in CSLCs of NSCLC remain unclear. This study aimed to identify the biological characteristics of CSLCs and the role of PHF5A in maintaining stemness of NSCLC. METHODS: H1299-spheres and A549-spheres were obtained by oncosphere-forming assay and CSLCs by flow cytometry. Expression of CD133, aldehyde dehydrogenase isoform 1, E-cadherin, vimentin, PHF5A, and histone deacetylase 8 (HDAC8) was tested using immunofluorescence staining, qRT-PCR, and Western blotting. CCK-8 and Transwell assays were employed to determine proliferation, migration, and invasion ability of CSLCs and adherent monolayer cells in NSCLC. We regulated PHF5A expression and HDAC activity in CSLCs to explore the mechanism of PHF5A in stemness maintenance and analyzed expression of target proteins in NSCLC tissues. RESULTS: Compared with monolayer cells, CSLCs showed a decreased response to cisplatin-mediated inhibition of proliferation, increased migration and invasion, and high expression of PHF5A and HDAC8, accompanied by EMT marker alterations. Targeted knockdown of PHF5A in CSLCs of NSCLC resulted in diminished stemness phenotypes and HDAC8 expression, whereas inhibition of HDAC activity affected stemness maintenance. Moreover, the expression of target proteins showed consistent changes in NSCLC tissues. CONCLUSIONS: Compared with monolayer cells, cancer stem-like phenotype properties of NSCLC were altered, PHF5A was involved in stemness maintenance of CSLCs, and this process may be related to the activation of HDAC8.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas de Ligação a RNA , Transativadores , Carcinoma Pulmonar de Células não Pequenas/genética , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia , Fenótipo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transativadores/genética , Transativadores/metabolismo
6.
Elife ; 112022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35834310

RESUMO

The hallmark event of the canonical transforming growth factor ß (TGFß) family signaling is the assembly of the Smad-complex, consisting of the common Smad, Smad4, and phosphorylated receptor-regulated Smads. How the Smad-complex is assembled and regulated is still unclear. Here, we report that active Arl15, an Arf-like small G protein, specifically binds to the MH2 domain of Smad4 and colocalizes with Smad4 at the endolysosome. The binding relieves the autoinhibition of Smad4, which is imposed by the intramolecular interaction between its MH1 and MH2 domains. Activated Smad4 subsequently interacts with phosphorylated receptor-regulated Smads, forming the Smad-complex. Our observations suggest that Smad4 functions as an effector and a GTPase activating protein (GAP) of Arl15. Assembly of the Smad-complex enhances the GAP activity of Smad4 toward Arl15, therefore dissociating Arl15 before the nuclear translocation of the Smad-complex. Our data further demonstrate that Arl15 positively regulates the TGFß family signaling.


Assuntos
Transativadores , Fator de Crescimento Transformador beta , Transdução de Sinais , Proteína Smad3/metabolismo , Proteína Smad4/metabolismo , Transativadores/metabolismo , Fator de Crescimento Transformador beta/metabolismo
7.
Methods Mol Biol ; 2537: 1-19, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35895255

RESUMO

Alternative pre-mRNA splicing allows for the production of multiple mRNAs from an individual gene, which not only expands the protein-coding potential of the genome but also enables complex mechanisms for the post-transcriptional control of gene expression. Regulation of alternative splicing entails a combinatorial interplay between an abundance of trans-acting splicing factors, cis-acting regulatory sequence elements and their concerted effects on the core splicing machinery. Given the extent and biological significance of alternative splicing in humans, it is not surprising that aberrant splicing patterns can cause or contribute to a wide range of diseases. In this introductory chapter, we outline the mechanisms that govern alternative pre-mRNA splicing and its regulation and discuss how dysregulated splicing contributes to human diseases affecting the motor system and the brain.


Assuntos
Processamento Alternativo , Precursores de RNA , Doença/genética , Humanos , Precursores de RNA/genética , Precursores de RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sequências Reguladoras de Ácido Nucleico , Transativadores/metabolismo
8.
Proc Natl Acad Sci U S A ; 119(28): e2119518119, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35867755

RESUMO

Early B cell factor 1 (EBF1) is a transcriptional factor with a variety of roles in cell differentiation and metabolism. However, the functional roles of EBF1 in tumorigenesis remain elusive. Here, we demonstrate that EBF1 is highly expressed in triple-negative breast cancer (TNBC). Furthermore, EBF1 has a pivotal role in the tumorigenicity and progression of TNBC. Moreover, we found that depletion of EBF1 induces extensive cell mitophagy and inhibits tumor growth. Genome-wide mapping of the EBF1 transcriptional regulatory network revealed that EBF1 drives TNBC tumorigenicity by assembling a transcriptional complex with HIF1α that fine-tunes the expression of HIF1α targets via suppression of p300 activity. EBF1 therefore holds HIF1α activity in check to avert extensive mitophagy-induced cell death. Our findings reveal a key function for EBF1 as a master regulator of mitochondria homeostasis in TNBC and indicate that targeting this pathway may offer alternative treatment strategies for this aggressive subtype of breast cancer.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Transativadores , Neoplasias de Mama Triplo Negativas , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
9.
Aliment Pharmacol Ther ; 56(5): 878-889, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35872575

RESUMO

BACKGROUND: Hepatitis B virus (HBV) infection is a serious global health burden. TRIM26 has been reported to affect hepatitis C virus replication. AIMS: To manifest the role of TRIM26 on HBV replication and explore if there are single-nucleotide polymorphisms (SNPs) in TRIM26 associated with response to pegylated interferon-alpha (PegIFNα) treatment in patients with chronic hepatitis B (CHB). METHODS: We investigated the effect and mechanism of TRIM26 on HBV replication in vitro. The association between SNPs in TRIM26 and PegIFNα treatment response was evaluated in two independent cohorts including 238 and 707 patients with HBeAg-positive CHB. RESULTS: Knockdown of TRIM26 increased, while overexpression of TRIM26 inhibited, HBV replication. Co-immunoprecipitation assays and immunofluorescence showed that TRIM26 interacted and co-localised with HBx. Co-transfection of HBx-HIS and TRIM26-FLAG plasmids in Huh7 cells showed that TRIM26 inhibited the expression of HBx. Furthermore, TRIM26 inhibited HBV replication by mediating HBx ubiquitination degradation, and TRIM26 SPRY domain was responsible for the interaction and degradation of HBx. Besides, IFN increased TRIM26 expression. TRIM26 rs116806878 was associated with response to PegIFNα in two CHB cohorts. Moreover, a polygenic score integrating TRIM26 rs116806878, STAT4 rs7574865 and CFB rs12614 (previously reported to be associated with response to PegIFNα) was related to response to PegIFNα in CHB. CONCLUSIONS: TRIM26 inhibits HBV replication; IFN promotes TRIM26 expression. TRIM26 exerts an inhibitory effect on HBx by promoting ubiquitin-mediated degradation of HBx. Furthermore, TRIM26 rs116806878 is a potential predictive biomarker of response to PegIFNα in patients with CHB.


Assuntos
Hepatite B Crônica , Hepatite B , Antígenos E da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/genética , Humanos , Polimorfismo Genético , Transativadores/genética , Transativadores/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais Reguladoras e Acessórias/genética , Replicação Viral/genética
10.
Commun Biol ; 5(1): 672, 2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35798971

RESUMO

The KH-type splicing regulatory protein (KHSRP) is an RNA-binding protein linked to decay of mRNAs with AU-rich elements. KHSRP was previously shown to destabilize Gap43 mRNA and decrease neurite growth in cultured embryonic neurons. Here, we have tested functions of KHSRP in vivo. We find upregulation of 1460 mRNAs in neocortex of adult Khsrp-/- mice, of which 527 bind to KHSRP with high specificity. These KHSRP targets are involved in pathways for neuronal morphology, axon guidance, neurotransmission and long-term memory. Khsrp-/- mice show increased axon growth and dendritic spine density in vivo. Neuronal cultures from Khsrp-/- mice show increased axon and dendrite growth and elevated KHSRP-target mRNAs, including subcellularly localized mRNAs. Furthermore, neuron-specific knockout of Khsrp confirms these are from neuron-intrinsic roles of KHSRP. Consistent with this, neurons in the hippocampus and infralimbic cortex of Khsrp-/- mice show elevations in frequency of miniature excitatory postsynaptic currents. The Khsrp-/- mice have deficits in trace conditioning and attention set-shifting tasks compared Khsrp+/+ mice, indicating impaired prefrontal- and hippocampal-dependent memory consolidation with loss of KHSRP. Overall, these results indicate that deletion of KHSRP impairs neuronal development resulting in alterations in neuronal morphology and function by changing post-transcriptional control of neuronal gene expression.


Assuntos
Consolidação da Memória , Proteínas de Ligação a RNA , Transmissão Sináptica , Transativadores , Animais , Camundongos , Camundongos Knockout , RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transativadores/genética , Transativadores/metabolismo
11.
J Antibiot (Tokyo) ; 75(8): 432-444, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35778609

RESUMO

Streptomyces represents an important reservoir for biologically active natural products. Understanding the biosynthetic mechanism and the mode of gene expression is important for enhanced metabolite production and evaluation of biological activities. This review provides an overview of biosynthetic studies investigating reveromycin and ß-carboline biomediators that enhanced the production of reveromycin in Streptomyces sp. SN-593 through activation of the LuxR family regulator. Furthermore, based on the optimal expression of a pathway specific regulator controlling the mevalonate pathway gene cluster, Streptomyces sp. SN-593 was developed as a platform for terpenoid compounds mass production.


Assuntos
Streptomyces , Carbolinas/metabolismo , Família Multigênica , Streptomyces/genética , Streptomyces/metabolismo , Terpenos/metabolismo , Transativadores/genética , Transativadores/metabolismo
12.
BMC Genomics ; 23(1): 483, 2022 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-35780101

RESUMO

BACKGROUND: Zinc finger protein 143(ZNF143), a member of the Krüppel C2H2-type zinc finger protein family, is strongly associated with cell cycle regulation and cancer development. A recent study suggested that ZNF143 plays as a transcriptional activator that promotes hepatocellular cancer (HCC) cell proliferation and cell cycle transition. However, the exact biological role of ZNF143 in liver regeneration and normal liver cell proliferation has not yet been investigated. METHODS: In our study, we constructed a stable rat liver cell line (BRL-3A) overexpressing ZNF143 and then integrated RNA-seq and Cleavage Under Targets and Tagmentation (CUT&Tag) data to identify the mechanism underlying differential gene expression. RESULTS: Our results show that ZNF143 expression is upregulated during the proliferation phase of liver regeneration after 2/3 partial hepatectomy (PH). The cell counting kit-8 (CCK-8) assay, EdU staining and RNA-seq data analyses revealed that ZNF143 overexpression (OE) significantly inhibited BRL-3A cell proliferation and cell cycle progression. We then performed CUT&Tag assays and found that approximately 10% of ZNF143-binding sites (BSs) were significantly changed genome-wide by ZNF143 OE. However, CCCTC-binding factor (CTCF) binding to chromatin was not affected. Interestingly, the integration analysis of RNA-seq and CUT&Tag data showed that some of genes affected by ZNF143 differential BSs are in the center of each gene regulation module. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that these genes are critical in the maintenance of cell identity. CONCLUSION: These results indicated that the expression level of ZNF143 in the liver is important for the maintenance of cell identity. ZNF143 plays different roles in HCC and normal liver cells and may be considered as a potential therapeutic target in liver disease.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Proliferação de Células/genética , Ratos , Transativadores/genética , Transativadores/metabolismo
13.
Cell Mol Biol (Noisy-le-grand) ; 67(5): 196-201, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35818253

RESUMO

This study aimed to investigate the inhibitory effect of miR-129-5p on colon cancer by targeting RSF1. For this purpose, real-time quantitative PCR was used to analyze whether the expression of miR-129-5p in colon cancer and adjacent normal tissues had an impact on the proliferation and apoptosis of cancer cells (CC). We evaluated the role of miR-129-5p by targeting RSF1 in colon cancer tissue in the experimental group. But in the control group, only miR-129-5p was considered as a protective factor. Finally, we retrospectively analyzed data of 56 cases of colon cancer patients admitted to our clinical department between January 2019 and December 2019. Twenty-eight cases were investigated through just miR-129-5p protective factors for cancer (group A). The other 28 cases were studied by miR-129-5p anti-cancer agent and a completed RSF1 carcinoma factors for cancer (group B). We evaluated the comparative analysis of the patient's age and gender, clinical indicators (including for the first time of hospitalization and postoperative hospital stay, three times of anal exhaust), and complications (including chills, vomiting, hypertension, diabetes). The results showed that miR-129-5p had a more substantial effect on the proliferation and apoptosis of CC by targeting RSF1.


Assuntos
Neoplasias do Colo , MicroRNAs , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Estudos Retrospectivos , Transativadores/genética , Transativadores/metabolismo
14.
Proc Natl Acad Sci U S A ; 119(30): e2200512119, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35857872

RESUMO

Epstein-Barr virus (EBV) is a human tumor virus which preferentially infects resting human B cells. Upon infection in vitro, EBV activates and immortalizes these cells. The viral latent protein EBV nuclear antigen 2 (EBNA2) is essential for B cell activation and immortalization; it targets and binds the cellular and ubiquitously expressed DNA-binding protein CBF1, thereby transactivating a plethora of viral and cellular genes. In addition, EBNA2 uses its N-terminal dimerization (END) domain to bind early B cell factor 1 (EBF1), a pioneer transcription factor specifying the B cell lineage. We found that EBNA2 exploits EBF1 to support key metabolic processes and to foster cell cycle progression of infected B cells in their first cell cycles upon activation. The α1-helix within the END domain was found to promote EBF1 binding. EBV mutants lacking the α1-helix in EBNA2 can infect and activate B cells efficiently, but activated cells fail to complete the early S phase of their initial cell cycle. Expression of MYC, target genes of MYC and E2F, as well as multiple metabolic processes linked to cell cycle progression are impaired in EBVΔα1-infected B cells. Our findings indicate that EBF1 controls B cell activation via EBNA2 and, thus, has a critical role in regulating the cell cycle of EBV-infected B cells. This is a function of EBF1 going beyond its well-known contribution to B cell lineage specification.


Assuntos
Linfócitos B , Infecções por Vírus Epstein-Barr , Antígenos Nucleares do Vírus Epstein-Barr , Regulação da Expressão Gênica , Herpesvirus Humano 4 , Proteínas Proto-Oncogênicas c-myc , Transativadores , Proteínas Virais , Linfócitos B/imunologia , Linfócitos B/virologia , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/metabolismo , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-myc/genética , Fase S , Transativadores/genética , Transativadores/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo
15.
Int J Mol Sci ; 23(14)2022 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-35887229

RESUMO

Previous RNA immunoprecipitation followed by proteomic approaches successfully demonstrated that Embryonic Lethal, Abnormal Vision, Drosophila-Like 1 (ELAVL1) interacts with hepatitis B virus (HBV)-derived RNAs. Although ELAVL family proteins stabilize AU-rich element (ARE)-containing mRNAs, their role in HBV transcription remains unclear. This study conducted loss-of-function assays of ELAVL1 for inducible HBV-replicating HepAD38 cells and HBx-overexpressed HepG2 cells. In addition, clinicopathological analyses in primary hepatocellular carcinoma (HCC) surgical samples were also conducted. Lentivirus-mediated short hairpin RNA knockdown of ELAVL1 resulted in a decrease in both viral RNA transcription and production of viral proteins, including HBs and HBx, probably due to RNA stabilization by ELAVL1. Cell growth of HepAD38 cells was more significantly impaired in ELAVL1-knockdown than those in the control group, with or without HBV replication, indicating that ELAVL1 is involved in proliferation by factors other than HBV-derived RNAs. Immunohistochemical analyses of 77 paired HCC surgical specimens demonstrated that diffuse ELAVL1 expression was detected more frequently in HCC tissues (61.0%) than in non-tumor tissues (27.3%). In addition, the abundant expression of ELAVL1 tended to affect postoperative recurrence in HBV-related HCC patients. In conclusion, ELAVL1 contributes not only to HBV replication but also to HCC cell growth. It may be a potent therapeutic target for HBV-related HCC treatment.


Assuntos
Carcinoma Hepatocelular , Hepatite B , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/metabolismo , Drosophila/genética , Células Hep G2 , Hepatite B/complicações , Hepatite B/genética , Hepatite B/metabolismo , Vírus da Hepatite B/fisiologia , Humanos , Neoplasias Hepáticas/metabolismo , Proteômica , RNA Viral/genética , RNA Viral/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transativadores/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo , Replicação Viral/genética
16.
Cell Death Dis ; 13(7): 645, 2022 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-35871061

RESUMO

Glioblastoma multiforme (GBM) is the most lethal type of craniocerebral gliomas. Glioma stem cells (GSCs) are fundamental reasons for the malignancy and recurrence of GBM. Revealing the critical mechanism within GSCs' self-renewal ability is essential. Our study found a novel circular RNA (circRPPH1) that was up-regulated in GSCs and correlated with poor survival. The effect of circRPPH1 on the malignant phenotype and self-renewal of GSCs was detected in vitro and in vivo. Mechanistically, UPF1 can bind to circRPPH1 and maintain its stability. Therefore, more existing circRPPH1 can interact with transcription factor ATF3 to further transcribe UPF1 and Nestin expression. It formed a feedback loop to keep a stable stream for stemness biomarker Nestin to strengthen tumorigenesis of GSCs continually. Besides, ATF3 can activate the TGF-ß signaling to drive GSCs for tumorigenesis. Knocking down the expression of circRPPH1 significantly inhibited the proliferation and clonogenicity of GSCs both in vitro and in vivo. The overexpression of circRPPH1 enhanced the self-renewal of GSCs. Our findings suggest that UPF1/circRPPH1/ATF3 maintains the potential self-renewal of GSCs through interacting with RNA-binding protein and activating the TGF-ß signal pathway. Breaking the feedback loop against self-renewing GSCs may represent a novel therapeutic target in GBM treatment.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Fator 3 Ativador da Transcrição , Neoplasias Encefálicas/patologia , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/metabolismo , Retroalimentação , Glioblastoma/patologia , Glioma/genética , Humanos , Células-Tronco Neoplásicas/metabolismo , Nestina/metabolismo , Fenótipo , RNA Helicases/genética , RNA Helicases/metabolismo , Transativadores/metabolismo , Fator de Crescimento Transformador beta/metabolismo
17.
J Exp Clin Cancer Res ; 41(1): 219, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35820928

RESUMO

BACKGROUND: The Hippo pathway functions as a tumor suppressor pathway in human cancers, while dysfunction of the Hippo pathway is frequently observed in malignancies. Although YAP/TAZ activity is tightly controlled by the phosphorylation cascade of the MST-LATS-YAP/TAZ axis, it is still unclear why the YAP/TAZ proteins are activated in human cancers despite Hippo pathway activation. Recent studies have suggested that in addition to phosphorylation, several other posttranslational modifications, including ubiquitination, also play critical roles in modulating TAZ function. METHODS: We used several gastric cancer cell lines and performed western blot analysis, real-time PCR, immunoprecipitation assays, and in vitro ubiquitination assays and established a xenograft mouse model. RESULTS: Here, by screening a DUB (deubiquitinase) siRNA library, we discovered that DUB1 functions as a critical modulator that facilitates gastric cancer stemness and progression by deubiquitinating and activating the TAZ protein. We also found that DUB1 expression was elevated in gastric cancer and that elevated DUB1 expression correlated with TAZ activation and poor survival. DUB1 associates with the TAZ protein and deubiquitinates TAZ at several lysine residues, which subsequently stabilizes TAZ and facilitates its function. CONCLUSIONS: Our study revealed a novel deubiquitinase in the Hippo/TAZ axis and identified one possible therapeutic target for Hippo-driven gastric cancer.


Assuntos
Via de Sinalização Hippo , Neoplasias Gástricas , Ubiquitina Tiolesterase , Proteínas de Sinalização YAP , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Enzimas Desubiquitinantes/metabolismo , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Processamento de Proteína Pós-Traducional , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Proteínas de Sinalização YAP/genética , Proteínas de Sinalização YAP/metabolismo
18.
Cell Mol Biol (Noisy-le-grand) ; 67(4): 1-9, 2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-35809308

RESUMO

LncRNA prostate cancer-associated transcript 1 (PCAT1) is a well-known oncogene, but the mechanisms of exosomes PCAT1 in colorectal cancer (CRC) remain largely unknown. Thus, the mechanisms of exosomes lncRNA PCAT1 were investigated. The expressions of exosomes lncRNA PCAT1 in tissues from stage 0-I and stage II-III CRC patients, and intestinal epithelial cell line FHC and two CRC cell lines, HT29 and HCT8 were measured by real-time quantitative PCR. The effects of lncRNA PCAT1 on adhesion and invasion of two CRC cell lines were investigated by cell-matrix adhesion and transwell assays. In addition, the target of PCAT1 (ZNF217) was validated using an RNA immune precipitation assay. Finally, the protein levels of MTA2, MTA3, SNAI1, and E-cadherin in normal participants, stage 0-I and stage II-III CRC patients, as well as two cell lines with stable ZNF217 knockdown were investigated by western blotting. The plasma exosomal lncRNA PCAT1 was found to be significantly increased in the CRC tissues and cell lines. In addition, lncRNA PCAT1 knockdown significantly inhibited the adhesion and invasion of HT29 and HCT8 cells. RIP assay results showed lncRNA PCAT1 could target ZNF217, and downregulation of lncRNA PCAT1 could decrease the protein expressions of ZNF217 in two CRC cells lines. Moreover, ZNF217 knockdown significantly decreased MTA2, MTA3, and SNAI1 expressions, but increased E-cadherin expressions in both CRC cells lines. Exosomal lncRNA PCAT1 can promote the adhesion and invasion of CRC cells, and PCAT1 overexpression may lead to ZNF217 upregulation that regulates EMT-related MTA2/MTA3/Snai1/E-cadherin signaling.


Assuntos
Neoplasias Colorretais , RNA Longo não Codificante , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Masculino , Proteínas de Neoplasias/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição da Família Snail , Transativadores/genética , Transativadores/metabolismo
19.
Front Immunol ; 13: 921366, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35774793

RESUMO

Activin A, a critical member of the transforming growth factor-ß (TGF-ß) superfamily, is a pluripotent factor involved in allergies, autoimmune diseases, cancers and other diseases with immune disorder. Similar to its family member, TGF-ß, activin A also transmits signals through SMAD2/SMAD3, however, they bind to distinct receptors. Recent studies have uncovered that activin A plays a pivotal role in both innate and adaptive immune systems. Here we mainly focus its effects on activation, differentiation, proliferation and function of cells which are indispensable in the immune system and meanwhile make some comparisons with those of TGF-ß.


Assuntos
Transativadores , Fator de Crescimento Transformador beta , Ativinas/metabolismo , Transdução de Sinais/fisiologia , Transativadores/metabolismo , Fator de Crescimento Transformador beta/metabolismo
20.
Development ; 149(13)2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35708349

RESUMO

Pancreatic and duodenal homeobox 1 (PDX1) is crucial for pancreas organogenesis, yet the dynamic changes in PDX1 binding in human or mouse developing pancreas have not been examined. To address this knowledge gap, we performed PDX1 ChIP-seq and single-cell RNA-seq using fetal human pancreata. We integrated our datasets with published datasets and revealed the dynamics of PDX1 binding and potential cell lineage-specific PDX1-bound genes in the pancreas from fetal to adult stages. We identified a core set of developmentally conserved PDX1-bound genes that reveal the broad multifaceted role of PDX1 in pancreas development. Despite the well-known dramatic changes in PDX1 function and expression, we found that PDX1-bound genes are largely conserved from embryonic to adult stages. This points towards a dual role of PDX1 in regulating the expression of its targets at different ages, dependent on other functionally congruent or directly interacting partners. We also showed that PDX1 binding is largely conserved in mouse pancreas. Together, our study reveals PDX1 targets in the developing pancreas in vivo and provides an essential resource for future studies on pancreas development.


Assuntos
Genes Homeobox , Proteínas de Homeodomínio , Animais , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Pâncreas , Transativadores/genética , Transativadores/metabolismo , Transcriptoma/genética
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