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1.
Biochem Biophys Res Commun ; 521(4): 933-938, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31718799

RESUMO

Neonatal hypoxic-ischemic encephalopathy (HIE) often leads to neonatal death or severe, irreversible neurological deficits. Pathologically, the occurrence of massive cell death and subsequent inflammation suggested that pyroptosis, an inflammation associated programed cell death, might play a role in HIE. Here, by measuring changes of key molecules in pyroptosis pathway in HIE patients, we discovered that their elevation levels tightly correlate with the severity of HIE. Next, we demonstrated that application of MCC950, a small molecule to inhibit NLRP3 inflammasome and thus pyroptosis, substantially alleviated pyroptosis and the injury severity in rats with neonatal hypoxic-ischemic brain damage (HIBD). Mechanistically, we showed that NLRP-3/caspase-1/GSDMD axis is required for microglia pyroptosis and activation. Our data demonstrated that microglia mediated pyroptosis played a crucial role in neonatal HIE, which shed lights into the development of intervention avenues targeting pyroptosis to treat HIE and traumatic brain injuries.

2.
Autophagy ; 15(9): 1506-1522, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30806153

RESUMO

Aberrant CTNNB1 signaling is one of the fundamental processes in cancers, especially colorectal cancer (CRC). Here, we reported that TRAF6, an E3 ubiquitin ligase important for inflammatory signaling, inhibited epithelial-mesenchymal transition (EMT) and CRC metastasis through driving a selective autophagic CTNNB1 degradation machinery. Mechanistically, TRAF6 interacted with MAP1LC3B/LC3B through its LC3-interacting region 'YxxL' and catalyzed K63-linked polyubiquitination of LC3B. The K63-linked ubiquitination of LC3B promoted the formation of the LC3B-ATG7 complex and was critical to the subsequent recognition of CTNNB1 by LC3B for the selective autophagic degradation. However, TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. Clinically, decreased expression of TRAF6 was associated with elevated GSK3B protein levels and activity and reduced overall survival in CRC patients. Pharmacological inhibition of GSK3B activity stabilized the TRAF6 protein, promoted CTNNB1 degradation, and effectively suppressed EMT and CRC metastasis. Thus, targeting TRAF6 and its pathway may be meaningful for treating advanced CRC. Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; AOM: azoxymethane; ATG5: autophagy related 5; ATG7: autophagy related 7; Baf A1: bafilomycin A1; BECN1: beclin 1; CoIP: co-immunoprecipitation; CQ: chloroquine; CRC: colorectal cancer; CTNNB1/ß-catenin: catenin beta 1; DSS: dextran sodium sulfate; EMT: epithelial-mesenchymal transition; FBS: fetal bovine serum; GFP: green fluorescent protein; GSK3B/GSK3ß: glycogen synthase kinase 3 beta; IgG: Immunoglobulin G; IHC: immunohistochemistry; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; RFP: red fluorescent protein; RT: room temperature; shRNA: short hairpin RNA; siRNA: small interfering RNA; TRAF6: TNF receptor-associated factor 6; WT: wild-type; ZEB1: zinc finger E-box binding homeobox 1.

3.
J Hematol Oncol ; 11(1): 95, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30016968

RESUMO

BACKGROUND: Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC. METHODS: Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression. RESULTS: Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC. CONCLUSIONS: Our study functionally links Ube2v1, an E2 member in the ubiquitin-proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.


Assuntos
Neoplasias Colorretais/metabolismo , Sirtuína 1/metabolismo , Fatores de Transcrição/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Autofagia/fisiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Epigênese Genética , Transição Epitelial-Mesenquimal , Xenoenxertos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Ubiquitinação
4.
Cancer Res ; 76(13): 3813-25, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27325643

RESUMO

The Hippo-Yap pathway conveys oncogenic signals, but its regulation during cancer development is not well understood. Here, we identify the nuclear receptor RARγ as a regulator of the Hippo-Yap pathway in colorectal tumorigenesis and metastasis. RARγ is downregulated in human colorectal cancer tissues, where its expression correlates inversely with tumor size, TNM stage, and distant metastasis. Functional studies established that silencing of RARγ drove colorectal cancer cell growth, invasion, and metastatic properties both in vitro and in vivo Mechanistically, RARγ controlled Hippo-Yap signaling to inhibit colorectal cancer development, acting to promote phosphorylation and binding of Lats1 to its transcriptional coactivator Yap and thereby inactivating Yap target gene expression. In clinical specimens, RARγ expression correlated with overall survival outcomes and expression of critical Hippo-Yap pathway effector molecules in colorectal cancer patients. Collectively, our results defined RARγ as tumor suppressor in colorectal cancer that acts by restricting oncogenic signaling by the Hippo-Yap pathway, with potential implications for new approaches to colorectal cancer therapy. Cancer Res; 76(13); 3813-25. ©2016 AACR.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/patologia , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores do Ácido Retinoico/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Western Blotting , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Técnicas Imunoenzimáticas , Metástase Linfática , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Estadiamento de Neoplasias , Fosfoproteínas/genética , Prognóstico , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores do Ácido Retinoico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Fatores de Transcrição , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Inflamm (Lond) ; 13: 4, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26839514

RESUMO

BACKGROUND: Nur77, a key member of the NR4A receptor subfamily, is involved in the regulation of inflammation and immunity. However, the in vivo regulatory roles of Nur77 in sepsis and the mechanisms involved remains largely elusive. In this study, we used Nur77-deficient (Nur77(-/-)) mice and investigated the function of Nur77 in sepsis. FINDINGS: Compared to wild-type (Nur77(+/+)) mice, Nur77(-/-) mice are more susceptible to LPS-induced sepsis and acute liver inflammation. Mechanistically, we observed that Nur77 can interact with TRAF6, a crucial adaptor molecule in the Toll-like receptor-interleukin 1 receptor (TLR-IL-1R) signalling pathway, in in vivo mouse model of sepsis. The interaction may affect TRAF6 auto-ubiquitination, thereby inhibiting NF-κB activation and pro-inflammatory cytokines production. CONCLUSIONS: These in vivo observations reveals an important protective role for Nur77 in LPS-induced sepsis through its regulation to TRAF6 signalling, and highlights the potential clinical application of Nur77 as a molecular target in prevention and/or treatment of sepsis.

6.
Cancer Res ; 76(1): 83-95, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26669864

RESUMO

Ubiquitin specific protease 4 (USP4) is a deubiquitinating enzyme with key roles in the regulation of p53 and TGFß signaling, suggesting its importance in tumorigenesis. However, the mechanisms and regulatory roles of USP4 in cancer, including colorectal cancer, remain largely elusive. Here, we present the first evidence that USP4 regulates the growth, invasion, and metastasis of colorectal cancer. USP4 expression was significantly elevated in colorectal cancer tissues and was significantly associated with tumor size, differentiation, distant metastasis, and poor survival. Knockdown of USP4 diminished colorectal cancer cell growth, colony formation, migration, and invasion in vitro and metastasis in vivo. Importantly, we found that phosphatase of regenerating liver-3 (PRL-3) is indispensable for USP4-mediated oncogenic activity in colorectal cancer. Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination. This resulted in activation of Akt and reduction of E-cadherin, critical regulators of cancer cell growth and metastasis. Examination of clinical samples confirmed that USP4 expression positively correlates with PRL-3 protein expression, but not mRNA transcript levels. Taken together, our results demonstrate that aberrant expression of USP4 contributes to the development and progression of colorectal cancer and reveal a critical mechanism underlying USP4-mediated oncogenic activity. These observations suggest that the potential of harnessing proteolytic degradation processes for therapeutic manipulation may offer a much-needed new approach for improving colorectal cancer treatment strategies.


Assuntos
Neoplasias Colorretais/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Células CACO-2 , Carcinogênese , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Células HCT116 , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Transdução de Sinais , Proteases Específicas de Ubiquitina , Ubiquitinação
7.
J Pathol ; 238(3): 457-69, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26564988

RESUMO

Nur77, an immediate-early response gene, participates in a wide range of biological functions. Its human homologue, NUR77, is known by several names and has the HGNC-approved gene symbol NR4A1. However, the role of Nur77 in inflammatory bowel disease (IBD) and its underlying mechanisms remain elusive. Here, using public data from the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) on the most recent genome-wide association studies (GWAS) for ulcerative colitis (UC) and Crohn's disease (CD), we found that genetic variants of the NUR77 gene are associated with increased risk for both UC and CD. Accordingly, Nur77 expression was significantly reduced in colon tissues from patients with UC or CD and mice treated with DSS. Nur77 deficiency increased the susceptibility of mice to DSS-induced experimental colitis and prevented intestinal recovery, whereas treatment with cytosporone B (Csn-B), an agonist for Nur77, significantly attenuated excessive inflammatory response in the DSS-induced colitis mouse model. Mechanistically, NUR77 acts as a negative regulator of TLR-IL-1R signalling by interacting with TRAF6. This interaction prevented auto-ubiquitination and oligomerization of TRAF6 and subsequently inhibited NF-κB activation and pro-inflammatory cytokine production. Taken together, our GWAS-based analysis and in vitro and in vivo studies have demonstrated that Nur77 is an important regulator of TRAF6/TLR-IL-1R-initiated inflammatory signalling, and loss of Nur77 may contribute to the development of IBD, suggesting Nur77 as a potential target for the prevention and treatment of IBD.


Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Receptores de Interleucina-1/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Receptores Toll-Like/metabolismo , Adulto , Idoso , Animais , Colo/metabolismo , Sulfato de Dextrana/farmacologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Fenilacetatos/farmacologia , Estudos Prospectivos , Transdução de Sinais/fisiologia
8.
J Inflamm (Lond) ; 12: 40, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26113803

RESUMO

BACKGROUND: Nur77, an orphan member of the nuclear receptor superfamily, has been implicated in the regulation of inflammation. However, the in vivo function of Nur77 remains largely unexplored. In the current study, we investigated the role of Nur77 in inflammation and immunity in mice. FINDINGS: We found that elderly 8-month-old Nur77-deficient mice (Nur77(-/-)) developed systemic inflammation. Compared to wild-type (WT) mice (Nur77(+/+)), Nur77(-/-) mice showed splenomegaly, severe infiltration of inflammatory cells in several organs including liver, lung, spleen and kidney, increased hyperplasia of fibrous tissue in the lung and enlargement of kidney glomeruli. Additionally, Nur77(-/-) mice had increased production of pro-inflammatory cytokines and immunoglobulin, and elicited pro-inflammatory M1-like polarization in macrophages as revealed by increased expression of CXCL11 and INDO, and decreased expression of MRC1. CONCLUSIONS: These in vivo observations provide evidence for a pivotal role for Nur77 in the regulation of systemic inflammation and emphasize the pathogenic significance of Nur77 in vivo.

9.
Carcinogenesis ; 35(11): 2474-84, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25064356

RESUMO

Nur77, an orphan member of the nuclear receptor superfamily, has been implicated in tumorigenesis. However, its contributions to colorectal cancer (CRC) invasion and metastasis are largely under characterized. Here, we present the first evidence that the invasion and metastasis of CRC is regulated by Nur77. High expression of Nur77 was observed in clinical CRC tissues, and this elevated expression was significantly associated with advanced tumor, lymph nodes, distant metastasis stage (P = 0.003), lymph node metastasis (P = 0.001) and poor survival (P = 0.03). Overexpression of Nur77 in CRC cells enhanced cell invasion in vitro, whereas knockdown of Nur77 diminished cell invasion and metastasis both in vitro and in vivo. In studying the possible mechanism by which overexpression of Nur77 contributes to CRC invasion and metastasis, we observed that the nuclear protein Nur77 promoted the expression of matrix metalloproteinase (MMP)-9, a novel downstream target of Nur77, and subsequently decreased the expression of E-cadherin. Examination of clinical samples further showed that Nur77 expression is positively correlated with MMP-9, whereas negatively correlated with E-cadherin. Interestingly, Nur77-mediated CRC invasion via MMP-9 and E-cadherin could be mimicked by some metastasis-inducible factors including hypoxia and prostaglandin E2. Collectively, our study demonstrated that Nur77 could promote the invasion and metastasis of CRC cells through regulation of MMP-9/E-cadherin signaling. These observations provide a possible new strategy for potentially treating or preventing the metastasis of CRC through targeting of Nur77.


Assuntos
Caderinas/biossíntese , Carcinogênese/genética , Neoplasias Colorretais/genética , Metaloproteinase 9 da Matriz/biossíntese , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Caderinas/genética , Movimento Celular/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Metástase Neoplásica , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Transdução de Sinais/genética
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