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1.
PLoS One ; 15(1): e0221851, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31961897

RESUMO

BACKGROUND: There is currently no effective treatment for promoting regeneration of injured nerves in patients who have sustained injury to the central nervous system such as spinal cord injury. Chondroitinase ABC is an enzyme, which promotes neurite outgrowth and regeneration. It has shown considerable promise as a therapy for these conditions. The aim of the study is to determine if targeting chondroitinase ABC expression to the neuronal axon can further enhance its ability to promote axon outgrowth. Long-distance axon regeneration has not yet been achieved, and would be a significant step in attaining functional recovery following spinal cord injury. METHODOLOGY/PRINCIPAL FINDINGS: To investigate this, neuronal cultures were transfected with constructs encoding axon-targeted chondroitinase, non-targeted chondroitinase or GFP, and the effects on neuron outgrowth and sprouting determined on substrates either permissive or inhibitory to neuron regeneration. The mechanisms underlying the observed effects were also explored. Targeting chondroitinase to the neuronal axon markedly enhances its ability to promote neurite outgrowth. The increase in neurite length is associated with an upregulation of ß-integrin staining at the axonal cell surface. Staining for phosphofocal adhesion kinase, is also increased, indicating that the ß-integrins are in an activated state. Expression of chondroitinase within the neurons also resulted in a decrease in expression of PTEN and RhoA, molecules which present a block to neurite outgrowth, thus identifying two of the pathways by which ChABC promotes neurite outgrowth. CONCLUSIONS / SIGNIFICANCE: The novel finding that targeting ChABC to the axon significantly enhances its ability to promote neurite extension, suggests that this may be an effective way of promoting long-distance axon regeneration following spinal cord injury. It could also potentially improve its efficacy in the treatment of other pathologies, where it has been shown to promote recovery, such as myocardial infarction, stroke and Parkinson's disease.


Assuntos
Condroitina ABC Liase/genética , Regeneração Nervosa/genética , Crescimento Neuronal/genética , Traumatismos da Medula Espinal/genética , Animais , Axônios/metabolismo , Condroitina ABC Liase/antagonistas & inibidores , Regulação da Expressão Gênica/genética , Humanos , Neuritos/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , PTEN Fosfo-Hidrolase/genética , Recuperação de Função Fisiológica/genética , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Proteína rhoA de Ligação ao GTP/genética
2.
Zhonghua Bing Li Xue Za Zhi ; 48(10): 784-790, 2019 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-31594043

RESUMO

Objective: To investigate the histological features and prognostic factors of angioimmunoblastic T-cell lymphoma (AITL). Methods: The pathological data of 62 patients with AITL with complete follow-up information were retrospectively collected and analyzed from Changhai Hospital during September 2012 and September 2017. Histological and immunohistochemical (IHC) examination, in situ hybridization (ISH), and single nucleotide polymorphisms (SNP) gene mutation analysis were done. Subgroup evaluation with histology, IHC, ISH, SNP gene mutation, and association with clinical progression were performed. Results: The cohort included 62 cases of AITL, including 46 males and 16 females patients, with a median age of 64 years. Follicular dendritic cells (FDC) area showed significantly expansion (≥30%) in 40 cases; increased plasma cells (≥10%) was seen in 37 cases; B cells were distributed around blood vessels in 37 cases; and increased p53 mutation positive cells (≥40%) were seen in 39 cases; high Ki-67 index (≥40%) was seen in 39 cases; RHOA mutation was seen in 19 cases; TET2 mutation was seen in 9 cases. Overall survival analysis showed these factors were significantly correlated with tumor prognosis (P<0.05). Multivariate analysis showed that CD38 positive cells<10%, Ki-67≥40%, RHOA and TET2 mutations were risk factors associated with overall survival. Conclusions: AITL could be divided into two different prognostic groups, low-grade and high-grade, with statistically significance outcome, based on the FDC area expansion, degree of plasma cell proliferation, B cells distribution pattern combined with gene mutations and clinical progression. Low-grade malignant group progresses slowly, and high-grade malignant group is highly invasive.


Assuntos
Linfadenopatia Imunoblástica/patologia , Linfoma de Células T/patologia , Proteínas de Ligação a DNA/genética , Células Dendríticas , Feminino , Humanos , Linfadenopatia Imunoblástica/diagnóstico , Hibridização In Situ , Linfoma de Células T/diagnóstico , Masculino , Pessoa de Meia-Idade , Plasmócitos , Polimorfismo de Nucleotídeo Único , Prognóstico , Proteínas Proto-Oncogênicas/genética , Estudos Retrospectivos , Proteína rhoA de Ligação ao GTP/genética
3.
Nat Genet ; 51(10): 1438-1441, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570889

RESUMO

Hypopigmentation along Blaschko's lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. Here we show that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Our findings pave the way toward elucidating the etiology of pigmentary mosaicism and highlight the role of RHOA in human development and disease.


Assuntos
Mosaicismo , Mutação , Síndromes Neurocutâneas/etiologia , Pigmentação da Pele/genética , Zigoto , Proteína rhoA de Ligação ao GTP/genética , Humanos , Síndromes Neurocutâneas/patologia
4.
Elife ; 82019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577226

RESUMO

EphA/ephrin signaling regulates axon growth and guidance of neurons, but whether this process occurs also independently of ephrins is unclear. We show that presenilin-1 (PS1)/γ-secretase is required for axon growth in the developing mouse brain. PS1/γ-secretase mediates axon growth by inhibiting RhoA signaling and cleaving EphA3 independently of ligand to generate an intracellular domain (ICD) fragment that reverses axon defects in PS1/γ-secretase- and EphA3-deficient hippocampal neurons. Proteomic analysis revealed that EphA3 ICD binds to non-muscle myosin IIA (NMIIA) and increases its phosphorylation (Ser1943), which promotes NMIIA filament disassembly and cytoskeleton rearrangement. PS1/γ-secretase-deficient neurons show decreased phosphorylated NMIIA and NMIIA/actin colocalization. Moreover, pharmacological NMII inhibition reverses axon retraction in PS-deficient neurons suggesting that NMIIA mediates PS/EphA3-dependent axon elongation. In conclusion, PS/γ-secretase-dependent EphA3 cleavage mediates axon growth by regulating filament assembly through RhoA signaling and NMIIA, suggesting opposite roles of EphA3 on inhibiting (ligand-dependent) and promoting (receptor processing) axon growth in developing neurons.


Assuntos
Axônios/fisiologia , Miosina não Muscular Tipo IIA/metabolismo , Presenilina-1/metabolismo , Receptor EphA3/metabolismo , Animais , Células Cultivadas , Humanos , Camundongos , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/metabolismo
5.
Rinsho Ketsueki ; 60(9): 1221-1228, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597847

RESUMO

Gene and protein expression profiling has clarified that tumor cells in angioimmunoblastic T-cell lymphoma (AITL) have T follicular helper (TFH) cell characteristics. In AITL, typical genomic abnormalities have been reported that combine G17V RHOA mutations, gene mutations involved in epigenetic pathways, and those involved in T-cell receptor signal pathways. Besides AITL, some lymphomas display a TFH phenotype, prompting the proposal of a new disease classification encompassing those. Interestingly, lymphomas with TFH phenotype characteristics also share most genomic abnormalities with AITL. Furthermore, because AITL genomic abnormalities are highly disease specific, they can be used for diagnosis. Although AITL is a refractory disease, several new drugs have been approved for relapsed and refractory cases. Precision medicine targeting genomic aberrations characteristic of AITL is being investigated.


Assuntos
Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Humanos , Mutação , Fenótipo , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Linfócitos T Auxiliares-Indutores , Proteína rhoA de Ligação ao GTP/genética
6.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600977

RESUMO

A high incidence of hypersensitivity reactions (HSRs) largely limits the use of paclitaxel injection. Currently, these reactions are considered to be mediated by histamine release and complement activation. However, the evidence is insufficient and the molecular mechanism involved in paclitaxel injection-induced HSRs is still incompletely understood. In this study, a mice model mimicking vascular hyperpermeability was applied. The vascular leakage induced merely by excipients (polyoxyl 35 castor oil) was equivalent to the reactions evoked by paclitaxel injection under the same conditions. Treatment with paclitaxel injection could cause rapid histamine release. The vascular exudation was dramatically inhibited by pretreatment with a histamine antagonist. No significant change in paclitaxel injection-induced HSRs was observed in complement-deficient and complement-depleted mice. The RhoA/ROCK signaling pathway was activated by paclitaxel injection. Moreover, the ROCK inhibitor showed a protective effect on vascular leakage in the ears and on inflammation in the lungs. In conclusion, this study provided a suitable mice model for investigating the HSRs characterized by vascular hyperpermeability and confirmed the main sensitization of excipients in paclitaxel injection. Histamine release and RhoA/ROCK pathway activation, rather than complement activation, played an important role in paclitaxel injection-induced HSRs. Furthermore, the ROCK inhibitor may provide a potential preventive approach for paclitaxel injection side effects.


Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/metabolismo , Paclitaxel/efeitos adversos , Transdução de Sinais , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Biópsia , Ativação do Complemento/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Modelos Animais de Doenças , Hipersensibilidade a Drogas/patologia , Feminino , Liberação de Histamina , Masculino , Camundongos , Paclitaxel/administração & dosagem
7.
Acta Biochim Biophys Sin (Shanghai) ; 51(10): 1026-1033, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31553428

RESUMO

Ibuprofen, a medication in the nonsteroidal anti-inflammatory drug class, is widely used for treating inflammatory diseases such as osteoarthritis. It has been shown in recent years that ibuprofen has a strong effect on Ras homolog gene family, member A (RhoA) inhibition in multiple cell types. Our previous finding also demonstrated that interleukin-1ß (IL-1ß) increases filamentous actin (F-actin) of chondrocytes via RhoA pathway. Therefore, we hypothesized that ibuprofen may suppress the IL-1ß-induced F-actin upregulation in chondrocytes by inhibiting RhoA pathway. To this end, in this study, articular chondrocytes from New Zealand White rabbits were pretreated with 500 µM ibuprofen for 2 h, then with 10 ng/ml IL-1ß for 24 h. Results showed that pretreatment with ibuprofen inhibited the IL-1ß-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production, protected the chondrocyte phenotype from IL-1ß stimulation, and inhibited the IL-1ß-induced actin remodeling via RhoA signaling modulation. In conclusion, ibuprofen showed not only anti-inflammatory function, but also RhoA inhibition in articular chondrocytes.


Assuntos
Actinas/imunologia , Anti-Inflamatórios não Esteroides/farmacologia , Condrócitos/efeitos dos fármacos , Ibuprofeno/farmacologia , Interleucina-1beta/imunologia , Animais , Células Cultivadas , Condrócitos/imunologia , Condrócitos/patologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Coelhos , Proteína rhoA de Ligação ao GTP/imunologia
8.
Int J Mol Sci ; 20(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500276

RESUMO

In various models of chronic kidney disease, the amount and localization of Cx43 in the nephron is known to increase, but the intracellular pathways that regulate these changes have not been identified. Therefore, we proposed that: "In the model of renal damage induced by infusion of angiotensin II (AngII), a RhoA/ROCK-dependent pathway, is activated and regulates the abundance of renal Cx43". In rats, we evaluated: 1) the time-point where the renal damage induced by AngII is no longer reversible; and 2) the involvement of a RhoA/ROCK-dependent pathway and its relationship with the amount of Cx43 in this irreversible stage. Systolic blood pressure (SBP) and renal function (urinary protein/urinary creatinine: Uprot/UCrea) were evaluated as systemic and organ outcomes, respectively. In kidney tissue, we also evaluated: 1) oxidative stress (amount of thiobarbituric acid reactive species), 2) inflammation (immunoperoxidase detection of the inflammatory markers ED-1 and IL-1ß), 3) fibrosis (immune detection of type III collagen; Col III) and 4) activity of RhoA/ROCK (amount of phosphorylated MYPT1; p-MYPT1). The ratio Uprot/UCrea, SBP, oxidative stress, inflammation, amount of Cx43 and p-MYPT1 remained high 2 weeks after suspending AngII treatment in rats treated for 4 weeks with AngII. These responses were not observed in rats treated with AngII for less than 4 weeks, in which all measurements returned spontaneously close to the control values after suspending AngII treatment. Rats treated with AngII for 6 weeks and co-treated for the last 4 weeks with Fasudil, an inhibitor of ROCK, showed high SBP but did not present renal damage or increased amount of renal Cx43. Therefore, renal damage induced by AngII correlates with the activation of RhoA/ROCK and the increase in Cx43 amounts and can be prevented by inhibitors of this pathway.


Assuntos
Angiotensina II/efeitos adversos , Conexina 43/metabolismo , Nefropatias/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Creatinina/urina , Modelos Animais de Doenças , Regulação da Expressão Gênica , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/urina , Masculino , Estresse Oxidativo , Ratos , Transdução de Sinais , Fatores de Tempo
9.
Exp Mol Pathol ; 110: 104294, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31394087

RESUMO

BACKGROUND: The World Health Organization, in a 2016 revision, introduced recurrent genetic abnormalities for classifying mature T- and NK-cell neoplasms. However, the role of genetic analyses from lymph node aspiration cytology is still not elucidated. We hypothesize that the use of genetic analyses may increase the accuracy of diagnosis from cytological preparations. METHODS: Fifty-seven formalin-fixed paraffin-embedded (FFPE) samples were collected for next-generation sequencing (NGS) targeting potential driver mutations including TET2, DMN3TA, IDH2, RHOA, STAT3, and STAT5B. Competitive allele-specific TaqMan polymerase chain reaction (cast-PCR) was performed to validate the mutation status by using FFPE and preoperative fine needle aspiration cytology (FNAC) samples. RESULTS: Among these six candidate genes, only IDH2 and RHOA mutations were significantly more frequent in nodal subtypes, angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) (P = .002 and <0.001, respectively). All genes exhibited different mutation patterns except RHOA with a hotspot mutation involving the Gly17 residue. The RHOA G17V mutation was found in 15 (75%) of 20 AITL and two (22%) of nine PTCL, NOS. Cast-PCR using FFPE samples showed 100% concordance with NGS. Among 12 lymph node aspirates, the preliminary diagnoses were suspicious for lymphoma (3, 25%), atypical lymphoid cells (3, 25%) and benign/negative (6, 50%). Cast-PCR detected the RHOA G17V mutation in six (75%) of eight RHOA-mutated aspirates and revealed negative results in all (100%) of four wild-type aspirates, with an 83.3% (10/12) concordance comparing to FFPE samples. CONCLUSIONS: The RHOA G17V mutation serves as a useful biomarker for cytological assessment in AITL. The use of cast-PCR is valuable in the diagnosis of malignant lymphomas from cytological preparations, and thus avoiding the potential risks of invasive procedures.


Assuntos
Biomarcadores Tumorais/genética , Citodiagnóstico/métodos , Linfadenopatia Imunoblástica/diagnóstico , Linfoma de Células T/diagnóstico , Mutação , Proteína rhoA de Ligação ao GTP/genética , Análise Mutacional de DNA , Humanos , Linfadenopatia Imunoblástica/genética , Linfoma de Células T/genética , Prognóstico
10.
Mol Carcinog ; 58(11): 2065-2076, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31432570

RESUMO

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. As tumor metastasis is the leading cause of death in patients with CRC, it is important to elucidate the molecular mechanisms that drive CRC metastasis. Studies have shown a close relationship between Iroquois homeobox (IRX) family genes and multiple cancers, while the mechanism by which IRX5 promotes CRC metastasis is unclear. Therefore, we focused on the involvement of IRX5 in CRC metastasis. In this study, analyses of clinical data indicated that the expression of IRX5 was coincided with metastatic colorectal tumors tissues and was negatively correlated with the overall survival of patients with CRC. Functional analysis showed that IRX5 promoted the migration and invasion of CRC cells, accompanied by a large number of cellular protrusions. IRX5-overexpressing cells were more likely to form metastatic tumors in nude mice. Further analysis demonstrated that the core components of the RHOA/ROCK1/LIMK1 pathway were significantly inhibited in IRX5-overexpressing cells. Overexpression of LIMK1 effectively reversed the enhanced cellular motility caused by IRX5 overexpression. Moreover, we found that high levels of IRX5 in intestinal tissues were correlated with the inflammatory response. IRX5 was significantly increased in azoxymethane/dextran sodium sulfate intestinal tissue of mice and IRX5-overexpressing may also enhance chemokines CXCL1 and CXCL8. In summary, our findings suggested that IRX5 promoted CRC metastasis by inhibiting the RHOA-ROCK1-LIMK1 axis, which correlates with a poor prognosis.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Homeodomínio/genética , Inflamação/genética , Fatores de Transcrição/genética , Proteína rhoA de Ligação ao GTP/genética , Animais , Quimiocina CXCL1/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HT29 , Xenoenxertos , Humanos , Interleucina-8/genética , Intestinos/patologia , Quinases Lim/genética , Masculino , Camundongos , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Análise Serial de Tecidos , Quinases Associadas a rho/genética
11.
Results Probl Cell Differ ; 67: 81-93, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31435793

RESUMO

In vertebrate cells, the Golgi apparatus is located in close proximity to the centriole. The architecture of the Golgi/centriole complex depends on a multitude of factors, including the actin filament cytoskeleton. In turn, both the Golgi and centriole act as the actin nucleation centers. Actin organization and polymerization also depend on the small GTPase RhoA pathway. In this chapter, we summarize the most current knowledge on how the genetic, magnetic, or pharmacologic interference with RhoA pathway and actin cytoskeleton directly or indirectly affects architecture, structure, and function of the Golgi/centriole complex.


Assuntos
Actinas/metabolismo , Centríolos/metabolismo , Complexo de Golgi/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Citoesqueleto de Actina/metabolismo
12.
Elife ; 82019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31461398

RESUMO

Dendritic arbor architecture profoundly impacts neuronal connectivity and function, and aberrant dendritic morphology characterizes neuropsychiatric disorders. Here, we identify the adhesion-GPCR BAI1 as an important regulator of dendritic arborization. BAI1 loss from mouse or rat hippocampal neurons causes dendritic hypertrophy, whereas BAI1 overexpression precipitates dendrite retraction. These defects specifically manifest as dendrites transition from growth to stability. BAI1-mediated growth arrest is independent of its Rac1-dependent synaptogenic function. Instead, BAI1 couples to the small GTPase RhoA, driving late RhoA activation in dendrites coincident with growth arrest. BAI1 loss lowers RhoA activation and uncouples it from dendrite dynamics, causing overgrowth. None of BAI1's known downstream effectors mediates BAI1-dependent growth arrest. Rather, BAI1 associates with the Rho-GTPase regulatory protein Bcr late in development and stimulates its cryptic RhoA-GEF activity, which functions together with its Rac1-GAP activity to terminate arborization. Our results reveal a late-acting signaling pathway mediating a key transition in dendrite development.


Assuntos
Proteínas Angiogênicas/metabolismo , Proliferação de Células , Dendritos/metabolismo , Proteínas Proto-Oncogênicas c-bcr/metabolismo , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Células Cultivadas , Camundongos , Ratos
13.
Cells ; 8(7)2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319592

RESUMO

RhoA is a ubiquitously expressed cytoplasmic protein that belongs to the family of small GTPases. RhoA acts as a molecular switch that is activated in response to binding of chemokines, cytokines, and growth factors, and via mDia and the ROCK signaling cascade regulates the activation of cytoskeletal proteins, and other factors. This review aims to summarize our current knowledge on the role of RhoA as a general key regulator of immune cell differentiation and function. The contribution of RhoA for the primary functions of innate immune cell types, namely neutrophils, macrophages, and conventional dendritic cells (DC) to (i) get activated by pathogen-derived and endogenous danger signals, (ii) migrate to sites of infection and inflammation, and (iii) internalize pathogens has been fairly established. In activated DC, which constitute the most potent antigen-presenting cells of the immune system, RhoA is also important for the presentation of pathogen-derived antigen and the formation of an immunological synapse between DC and antigen-specific T cells as a prerequisite to induce adaptive T cell responses. In T cells and B cells as the effector cells of the adaptive immune system Rho signaling is pivotal for activation and migration. More recently, mutations of Rho and Rho-modulating factors have been identified to predispose for autoimmune diseases and as causative for hematopoietic malignancies.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Diferenciação Celular , Humanos , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/genética
14.
BMC Cancer ; 19(1): 713, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324164

RESUMO

BACKGROUND: Identification of molecular markers for early detection or prediction of metastasis is crucial for both management of HCC patient postoperative treatment and identify new therapeutic targets to inhibit HCC progression and metastasis. In the current study, we investigated the clinical correlation between Pin1, RhoA and RhoC and their association with HCC metastasis. METHODS: Using a randomized study design of primary HCC samples from 139 patients, we determined messenger RNA expression of Pin1, RhoA and RhoC and their prognostic value. RESULTS: Our findings demonstrated for the first time the clinical correlation of Pin1 in HCC metastasis. Pin1, RhoA and RhoC transcript levels were significantly higher in HCC specimens when compared with the paired adjacent non-tumorous liver. Pin1 overexpression was closely correlated with that of RhoA (R = 0.562, p < 0.001) and RhoC (R = 0.529, p < 0.001), and their co-overexpressions correlated with metastatic HCC (p = 0.000012) and poor recurrence-free survival of HCC patients (p < 0.00001), which showed better prognostic significance than either Pin1, RhoA or RhoC overexpression alone. Co-overexpressions of Pin1 + RhoA/RhoC were also an independent factor for predicting development of metastasis after curative resection in our multivariate regression model (p < 0.001). CONCLUSION: Pin1, RhoA and RhoC co-overexpressions are prognostic factor for metastatic HCC and predict poor recurrence-free survival.


Assuntos
Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Proteína de Ligação a GTP rhoC/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/cirurgia , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Cuidados Pós-Operatórios , Prognóstico , RNA Mensageiro/genética , Distribuição Aleatória , Adulto Jovem
15.
Nat Commun ; 10(1): 3196, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324767

RESUMO

The limited clinical response observed in high-grade serous ovarian cancer (HG-SOC) with high frequency of TP53 mutations (mutp53) might be related to mutp53-driven oncogenic pathway network. Here we show that ß-arrestin1 (ß-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows ß-arr1 to recruit mutp53 to the YAP-TEAD transcriptional complex upon activation of endothelin-1 receptors (ET-1R) in patient-derived HG-SOC cells and in cell lines bearing mutp53. In parallel, ß-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through ß-arr1 orchestrates the tethering of YAP and mutp53 to YAP/mutp53 target gene promoters, including EDN1 that ensures persistent signals. Treatment of patient-derived xenografts reveals synergistic antitumoral and antimetastatic effects of the dual ET-1R antagonist macitentan in combination with cisplatinum, shutting-down the ß-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ETAR/ß-arr1/YAP gene signature correlates with a worst prognosis in HG-SOC. These findings support effective combinatorial treatment for repurposing the ET-1R antagonists in HG-SOC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Neoplasias Ovarianas/metabolismo , Receptor de Endotelina A/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , beta-Arrestina 1/metabolismo , Animais , Antineoplásicos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Modelos Animais de Doenças , Endotelina-1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Camundongos Nus , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/farmacologia , Receptor de Endotelina A/efeitos dos fármacos , Sulfonamidas/farmacologia , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Arrestina 1/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
16.
Chem Biol Interact ; 311: 108749, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31325423

RESUMO

PURPOSE: Excessive proliferation, migration and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs) are the basis for the development of pulmonary vascular remodeling, and it is the driving force for pulmonary arterial hypertension (PAH). 18ß-glycyrrhetinic acid (18ß-GA) is the main active substance extracted from Chinese herbal medicine licorice, with outstanding anti-inflammatory, anti-oxidation and anti-proliferative effects. Our team found in previous studies that 18ß-GA has protective effects on monocrotaline-induced PAH in rats. However, the anti-angiogenic effect of 18ß-GA on PAH remains unclear. Therefore, in order to further investigate whether the beneficial effects of 18ß-GA on PAH are related to its antiproliferative effect, we conducted experiments in vivo and in vitro. METHODS AND RESULTS: In vivo, 18ß-GA relieved mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricular hypertrophy index, improving pulmonary remodeling. In vitro, 18ß-GA significantly inhibited PDGF-BB-induced proliferation and DNA synthesis of HPASMCs, blocking the progression of G0/G1 to S phase of the cell cycle. Furthermore, after treatment with 18ß-GA, the expression of Rho A, ROCK1, ROCK2 was decreased and ROCK activity was inhibited in HPASMC. In addition, 18ß-GA also attenuated PDGF-induced changes in p27kip1, Bax and Bcl-2. CONCLUSIONS: In summary, these results indicate that 18ß-GA regulates the activity of RhoA-ROCK signaling pathway, inhibits the proliferation of HPASMCs, and has potential value in the treatment of PAH.


Assuntos
Ácido Glicirretínico/análogos & derivados , Hipertensão Pulmonar/patologia , Substâncias Protetoras/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glicirretínico/farmacologia , Ácido Glicirretínico/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Monocrotalina/toxicidade , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Substâncias Protetoras/uso terapêutico , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
17.
J Exp Clin Cancer Res ; 38(1): 283, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262330

RESUMO

BACKGROUND: Mucins are key components of the mucosal barrier in the stomach that protects epithelia from carcinogenic effects of chronic inflammation. Analysis of The Cancer Genome Atlas database indicated that mucin-17 (MUC17) was more highly expressed in gastric cancer (GC) specimens, with favourable prognosis for patients. To explore the underlying mechanisms, we investigated the potential role of MUC17 in controlling chronic gastric inflammation. METHODS: We initially quantified the expression of MUC17 and inflammatory factor, as well as the association of MUC17 with survive in GC using immunohistochemistry. To establish how the inflammatory factors affect MUC17 expression, we explored luciferase reporter, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift (EMSA) assays. The role and mechanism that MUC17 plays in inflammation-induced cell proliferation was examined in AGS cells with reduced MUC17 expression and MKN45 cells overexpressing a truncated MUC17. RESULTS: We found MUC17 was induced by inflammatory cytokines in GC cells via CDX1upregulation. MUC17 thus inactivated NFκB to inhibit GC cell proliferation in response to pro-inflammatory cytokines. We also revealed that the function of MUC17 was dependent on its conserved epidermal growth factor domain and on downstream sequences to enable its interaction with myosin-9, resulting in a sustained regulatory feedback loop between myosin-9, p53, and RhoA, and then activation of p38 to negatively regulate the NFκB pathway in GC cells. This mechanism was also confirmed in vivo. CONCLUSIONS: Our study demonstrates MUC17 as a GC suppressor protein which has the therapeutic potential for human GC.


Assuntos
Proteínas Motores Moleculares/metabolismo , Mucinas/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Neoplasias Gástricas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Progressão da Doença , Retroalimentação Fisiológica , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Inflamação/metabolismo , Interleucina-8/metabolismo , Camundongos , Mucinas/genética , NF-kappa B/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
BMC Res Notes ; 12(1): 420, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311589

RESUMO

OBJECTIVE: The contribution of actomyosin contractile rings in the wound healing program of somatic cells as never been directly assessed. This contrast with the events characterising the wound healing response of in wounded Xenopus oocytes, in which formation and contraction of an actomyosin ring provides a platform for cytoskeletal repair and drives the restoration of proper plasma membrane composition at the site of injury. As such, we aimed to characterize, using high-resolution live-cell confocal microscopy, the cytoskeletal repair dynamics of HeLa cells. RESULTS: We confirm here that the F-actin enrichment that characterizes the late repair program of laser-wounded cells is mostly uniform and is not associated with co-enrichment of myosin-II or the formation of concentric zones of RhoA and Cdc42 activity.


Assuntos
Actinas/metabolismo , Membrana Celular/metabolismo , Mamíferos/metabolismo , Polimerização , Análise de Célula Única/métodos , Actomiosina/metabolismo , Animais , Citoesqueleto/metabolismo , Células HeLa , Humanos , Cinética , Microscopia Confocal , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
19.
Dev Cell ; 49(6): 819-820, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31211987

RESUMO

In this issue of Developmental Cell, Budnar and colleagues report how the scaffolding protein anillin uses cycles of transient binding interactions to enhance the residence time and signaling output of active RhoA to control actomyosin contractility at epithelial junctions and during cell division.


Assuntos
Proteínas Contráteis , Tato , Actomiosina , Cinética , Proteína rhoA de Ligação ao GTP
20.
Biotechnol Appl Biochem ; 66(5): 850-857, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31245891

RESUMO

The aim of this study was to investigate the protective effects of vitamin D (VD) against myocardial ischemia-reperfusion (I/R) injury in hearts. An I/R injury model was induced by left coronary artery ligation in Sprague-Dawley rats (in vivo) and Langendorff perfusion of isolated hearts (in vitro). The infarction areas were determined by triphenyltetrazolium chloride (TTC) staining. Changes in the ST segment, cardiac function, lactate dehydrogenase (LDH) activity, creatine kinase (CK) activity, inflammatory cytokine (interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α)) levels and the RhoA/ROCK/NF-ĸB pathway were tested in rats with I/R injury treated with or without VD. VD notably alleviated myocardial injury with decreased infarction areas and had a restorative effect on cardiac function, which was specifically manifested as a restored ST segment, increased myocardial contractility and increased coronary blood flow in the isolated hearts. The levels of CK and LDH were also suppressed by VD. In addition, VD significantly decreased the expression of inflammatory cytokines in rat sera and isolated hearts. The RhoA/ROCK/NF-κB pathway in I/R-injured rats was also obviously inhibited with VD treatment. The present study demonstrates that VD plays a protective role against myocardial injury by inhibiting inflammation through repressing the RhoA/ROCK/NF-κB pathway.


Assuntos
Inflamação/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Vitamina D/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Animais , Inflamação/metabolismo , Inflamação/patologia , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
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