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1.
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
2.
EMBO J ; 38(14): e99299, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31304629

RESUMO

The metastatic progression of cancer is a multi-step process initiated by the local invasion of the peritumoral stroma. To identify the mechanisms underlying colorectal carcinoma (CRC) invasion, we collected live human primary cancer specimens at the time of surgery and monitored them ex vivo. This revealed that conventional adenocarcinomas undergo collective invasion while retaining their epithelial glandular architecture with an inward apical pole delineating a luminal cavity. To identify the underlying mechanisms, we used microscopy-based assays on 3D organotypic cultures of Caco-2 cysts as a model system. We performed two siRNA screens targeting Rho-GTPases effectors and guanine nucleotide exchange factors. These screens revealed that ROCK2 inhibition triggers the initial leader/follower polarization of the CRC cell cohorts and induces collective invasion. We further identified FARP2 as the Rac1 GEF necessary for CRC collective invasion. However, FARP2 activation is not sufficient to trigger leader cell formation and the concomitant inhibition of Myosin-II is required to induce invasion downstream of ROCK2 inhibition. Our results contrast with ROCK pro-invasive function in other cancers, stressing that the molecular mechanism of metastatic spread likely depends on tumour types and invasion mode.


Assuntos
Adenocarcinoma/metabolismo , Técnicas de Cultura de Células/métodos , Neoplasias Colorretais/metabolismo , Quinases Associadas a rho/metabolismo , Adenocarcinoma/genética , Animais , Células CACO-2 , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Organoides/citologia , Organoides/metabolismo , RNA Interferente Pequeno/farmacologia , Quinases Associadas a rho/genética
3.
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
4.
Molecules ; 24(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31197105

RESUMO

Molecular hybridization has proven to be a successful multi-target strategy in the design and development of new antitumor agents. Based on this rational approach, we have planned hybrid molecules containing covalently linked pharmacophoric units, present individually in compounds acting as inhibitors of the cancer protein targets tubulin, human topoisomerase II and ROCK1. Seven new molecules, selected by docking calculation of the complexes with each of the proteins taken into consideration, have been efficiently synthesized starting from 2,3-dichloro-1,4-naphtoquinone or 6,7-dichloro-5,8-quinolinquinone. By screening the full National Cancer Institute (NCI) panel, including 60 human cancer cell lines, four molecules displayed good and sometimes better growth inhibition GI50 than the ROCK inhibitor Y-27632, the Topo II inhibitor podophyllotoxin and the tubulin inhibitor combretastatin A-4. The relative position of N,N heteroatoms in the structures of the tested compounds was crucial in affecting bioactivity and selectivity. Furthermore, compound 3 (2-(4-(2-hydroxyethyl)piperazin-1-yl)-3-(3,4,5-trimethoxyphenoxy)naphthalene-1,4-dione) emerged as the most active in the series, showing a potent and selective inhibition of breast cancer BT-549 cells (GI50 < 10 nM).


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase II/farmacologia , Moduladores de Tubulina/farmacologia , Amidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/genética , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Neoplasias/genética , Podofilotoxina/farmacologia , Piridinas/farmacologia , Quinolinas/síntese química , Quinolinas/química , Estilbenos/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Tubulina (Proteína)/química , Tubulina (Proteína)/genética , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/química , Quinases Associadas a rho/genética
5.
Cell Prolif ; 52(4): e12628, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31038266

RESUMO

OBJECTIVES: This research aims to verify that the long non-coding RNA differentiation antagonizing nonprotein coding RNA (LncRNA DANCR) could modulate the proliferation and metastasis of hepatocellular carcinoma (HCC), and it thus may work as a novel biomarker to render new orientation for early diagnosis and clinical therapy of HCC. MATERIALS AND METHODS: Firstly, qRT-PCR was used to detect the expression of genes including LncRNA DANCR and miR-27a-3p. Next, MTT assay, Ethynyldeoxyuridine (EdU) analysis and clone formation assay were used for investigating cell growth and proliferation. Meanwhile, transwell assay and wound healing assay were applied to evaluate the capacity of cell metastasis and motility, respectively. In addition, bioinformatic analysis and dual-luciferase reporter assay were applied to analyse molecular interaction. Next, we conducted immunofluorescence and Western blot for mechanic investigation. Last but not the least, xenograft tumours in nude mice were built by subcutaneously injecting Hep3B cells stably transfected with sh-NC and sh-DANCR to detect proliferation and SMMC-7721 cells stably transfected with sh-NC and sh-DANCR to investigate metastasis. RESULTS: The results of qRT-PCR and bioinformatic analysis revealed the high expression of DANCR in HCC. DANCR accelerated proliferation and metastasis of HCC cells and the knockdown of DANCR had the opposite effect. Meanwhile, xenograft tumours in sh-DANCR group grow slower and have smaller volumes compared with negative control group. Next, the antineoplastic effect of miR-27a-3p on cell growth and motility of HCC was confirmed. In addition, we clarified that DANCR acted as a ceRNA to decoy miR-27a-3p via mediating ROCK1/LIMK1/COFILIN1 pathway. In the end, we validated that DANCR/miR-27a-3p axis regulates EMT progression by cell immunofluorescence and Western blot. CONCLUSIONS: In a word, DANCR promotes HCC development and induces EMT by decoying miR-27a-3p to regulate ROCK1/LIMK1/COFILIN1 pathway.


Assuntos
Carcinoma Hepatocelular/genética , Transição Epitelial-Mesenquimal/genética , Quinases Lim/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Quinases Associadas a rho/genética , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus
6.
Mol Med Rep ; 19(6): 5153-5161, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059087

RESUMO

Parkinson's disease (PD) is a common progressive neurodegenerative disorder occurring in older individuals. Mechanistically, neuroinflammation is a central pathological change in the progression of PD. Activation of microglia is widely considered to be a major trigger for neuroinflammation. Certain microRNAs (miRs) are key factors in inhibiting or stimulating inflammation during the occurrence and development of PD, among which miR­195 may be a potential crucial biomarker. However, the underlying pathological mechanisms remain unclear. To investigate the pathogenesis of PD, lipopolysaccharide (LPS) was used to establish an in vitro model of microglia activation in the present study. It was revealed that miR­195 expression was decreased in LPS­stimulated BV2 cells, suggesting a potential mechanism of action of miR­195 on microglia activation. Furthermore, gain­ and loss­of­function experiments were performed by successful transfection of microglia with miR­195 mimics or inhibitors. The results demonstrated that miR­195 overexpression inhibited the release of pro­inflammatory cytokines, including inducible nitric oxide synthase, interleukin­6 (IL­6) and tumor necrosis factor­α, but induced the release of anti­inflammatory cytokines in LPS­treated BV2 cells, including IL­4 and IL­10. In addition, Rho­associated kinase 1 (ROCK1), which is negatively regulated by miR­195, was increased in LPS­stimulated BV2 cells. ROCK1 knockdown with small interfering RNA exhibited the same effect as miR­195 overexpression on regulating microglia status, suggesting that the miR­195/ROCK1 interaction serves a central role in inducing microglia activation. Furthermore, inhibition of ROCK1 impaired cell viability and proliferation but induced cell apoptosis in LPS­treated miR­195­deficient BV2 cells. The present results suggest that miR­195 is a potential therapeutic target for PD.


Assuntos
MicroRNAs/metabolismo , Quinases Associadas a rho/metabolismo , Animais , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inflamação , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/genética
7.
BMC Genomics ; 20(1): 409, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117934

RESUMO

BACKGROUND: Our previous study described the crucial role of Rho-associated coiled-coil containing-kinases (ROCK) in hepatocellular carcinoma (HCC). However, the potential significance of long noncoding RNA downstream of ROCK is largely unknown. Here, a comprehensive comparative bioinformatics analysis of a microarray of an MHCC-97H cell line overexpressing ROCK1 or ROCK2 was performed. RESULTS: Numerous lncRNAs and mRNAs were deregulated by Rho-associated coiled-coil containing kinases 1 and 2. These results were consistent with the qRT-PCR results. Compared with MHCC-97H-Con, which was transfected with a null vector, the GO analysis revealed differentially expressed mRNAs (DEmRNAs) in MHCC-97H-ROCK1 (ROCK1 was overexpressed) enriched in apoptotic cell clearance, the cyclooxygenase pathway and bone trabecula morphogenesis; the DEmRNAs in MHCC-97H-ROCK2 (ROCK2 was overexpressed) were enriched in VEGF production, chemokine-associated signaling pathways, acute inflammatory response and vasoconstriction. Compared with MHCC-97H-ROCK2, the DEmRNAs in MHCC-97H-ROCK1 were involved in the JAK-STAT cascade, the Akt signaling pathway and the activity of several different peptidases. The pathway analysis of ROCK1 and ROCK2 revealed an overlap in the VEGF signaling pathway, ECM-receptor interaction, and adhesion and differences in the PPAR signaling pathway and mismatch repair. The predicted targets of the differentially expressed lncRNA (DElncRNAs) were enriched in the p53 signaling pathway, Jak-STAT signaling pathway, etc. Several hub DElncRNAs were identified. CONCLUSIONS: ROCK1 and 2 modulate the expression of numerous mRNAs and lncRNAs and may participate in several signaling pathways in HCC. Several hub molecules were identified in the lncRNA-mRNA networks. Our results provide baseline data for ROCK1 and 2 regulation in HCC that might have implications for further research.


Assuntos
Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo , Quinases Associadas a rho/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , RNA Mensageiro/genética , Transdução de Sinais , Células Tumorais Cultivadas , Quinases Associadas a rho/genética
8.
Immunopharmacol Immunotoxicol ; 41(3): 446-454, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31124391

RESUMO

Context: Atherosclerosis is a chronic inflammatory disease in which the plaques were built up inside of the artery. Interleukin-8 (IL-8, CXCL8) is an inflammatory factor, known to play an important role in the development of atherosclerosis. G31P is an antagonist of the IL-8 receptor, which plays roles in vascular smooth muscle cell (VSMC) proliferation and migration. Objective: This study is to investigate the therapeutic effect of G31P on atherosclerosis through a mouse model. Materials and methods: A mouse model of atherosclerosis was generated through feeding the ApoE-/- mice with high fat diet for 12 weeks. G31P was injected subcutaneously into the mice. The levels of keratinocyte chemoattractant (KC), CXCR2, TNF-α, and IFN-γ were analyzed through ELISA. The expressions of MMP-2, MMP-9, PCNA, and Mef2a in aortic tissues were detected through RT-qPCR. In A7r5 cells, the levels of p-ERK, ROCK1, and ROCK2 were analyzed by western blot. Intracellular calcium levels were measured through Fluo-3 AM assay. Results and disccussion: G31P suppressed the abnormal lipid profile and decreased the levels of KC, MMP-2, MMP-9, PCNA, and Mef2a in a mouse model of atherosclerosis. In addition, G31P also inhibited the expressions of p-ERK, ROCK1, ROCK2, and decreased the calcium concentrations in A7r5 cells. Conclusions: These findings indicate the potential therapeutic effects of G31P in suppressing the development of atherosclerosis by antagonizing the IL-8 receptor. G31P inhibits the proliferation and migration of VSMCs through regulating the Rho-kinase, ERK, and calcium-dependent pathways.


Assuntos
Aorta/imunologia , Aterosclerose/tratamento farmacológico , Interleucina-8/farmacologia , Músculo Liso Vascular/imunologia , Miócitos de Músculo Liso/imunologia , Fragmentos de Peptídeos/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Animais , Aorta/patologia , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/imunologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Camundongos , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica/genética , Placa Aterosclerótica/imunologia , Placa Aterosclerótica/patologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/imunologia , Quinases Associadas a rho/genética , Quinases Associadas a rho/imunologia
9.
Front Biosci (Landmark Ed) ; 24: 1167-1177, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136973

RESUMO

miR-139 has a tumor suppressor effect in many tumors. Here, we examined the suppressive role of this miRNA and its target, ROCK1, in osteosarcoma (OS), a highly malignant bone tumor that mainly affects children and adolescents. The expression of miR-139 was down-regulated in OS. Overexpression of miR-139 significantly inhibited OS cell proliferation, migration, and invasion. Ectopic expression of miR-139 down-regulated ROCK1, a target of miR-139, by direct binding to its 3' untranslated region (3'UTR). Direct  siRNA-mediated silencing of ROCK1 exerted an inhibitory effect on OS cell proliferation and invasion similar to the effect of miR-139. ROCK1 transfection reversed the suppressive effect of miR-139 on OS cell proliferation and invasion. Both miR-139 and siRNA knockdown of ROCK1 significantly down-regulated ß-CATENIN and p-AKT and up-regulated E-CADHERIN and p53. The data provided here show that miR-139 exerts suppressive effects on proliferation and invasion of OS cells by targeting ROCK1.


Assuntos
Neoplasias Ósseas/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Osteossarcoma/genética , Quinases Associadas a rho/genética , Regiões 3' não Traduzidas/genética , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Interferência de RNA , Transplante Heterólogo , Carga Tumoral/genética , Quinases Associadas a rho/metabolismo
10.
Med Sci Monit ; 25: 3090-3099, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31026254

RESUMO

BACKGROUND In the pathogenesis and progression of prostate cancer, cell proliferation and cell migration results in tumor invasion and metastasis that is associated with patient morbidity and mortality. Rho-associated protein kinase (ROCK) has previously been shown to be upregulated in prostate cancer, but its biological role remains poorly understood. This study aimed to investigate the role of ROCK in the proliferation and migration of PC-3 and DU145 prostate cancer cells and to identify the possible targets involved by knockdown of ROCK1 and ROCK2 RNA expression. MATERIAL AND METHODS An RNA interference (RNAi) assay was performed to silence the expression of ROCK1 and ROCK2 in the PC-3 and DU145 human prostate cancer cell lines. Cells were also treated with a specific ROCK inhibitor, Y27632. A cell counting kit-8 (CCK-8) assay was used to determine the proliferation rate of prostate cancer cells, and cell migration and invasion assays were performed. Western blot and polymerase chain reaction were used to measure protein and RNA expression levels. RESULTS In PC-3 and DU145 prostate cancer cells, knockdown of ROCK1 and ROCK2 reduced cell migration and invasion. ROCK1 and ROCK2 regulated cell proliferation in PC-3 and DU145 prostate cancer cells. Protein levels of phosphorylated LIM kinase 1 (p-LIMK1) and matrix metalloproteinase-2 (MMP-2) were reduced in ROCK1 and ROCK2 siRNA transfected cells. CONCLUSIONS In PC-3 and DU145 human prostate cancer cells, ROCK promoted cell proliferation and migration by targeting LIMK1 and MMP-2.


Assuntos
Quinases Lim/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Neoplasias da Próstata/enzimologia , Quinases Associadas a rho/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Nus , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Transdução de Sinais , Quinases Associadas a rho/genética
11.
Biomed Res Int ; 2019: 9053295, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30886866

RESUMO

Paeoniflorin (PF), as one of the important valid natural compounds of the total glucosides of peony, has displayed a potential effect in cancer prevention and treatment. Aggressive migration and invasion, as an important process, can contribute to tumor progression through infiltrating the surround normal tissue. Actin cytoskeleton rearrangement plays a key role in cells migration and invasion, involving multiple signal pathways. HGF/c-Met signal, as an important couple of oncoprotein, has been demonstrated to regulate actin cytoskeleton rearrangement. In our study, we aim to explore whether paeoniflorin can inhibit migration and invasion and actin cytoskeleton rearrangement via regulation of HGF/c-Met/RhoA/ROCK signal. Various approaches were applied to demonstrate the mechanism of paeoniflorin-mediated anticancer effect, including cell wound healing assay, invasion assay, immunofluorescence staining and transfection, and western blotting. We observed that paeoniflorin inhibited HGF-induced migration and invasion and actin cytoskeleton rearrangement in glioblastoma cells. Furthermore, the inhibition of HGF-induced migration and invasion and actin cytoskeleton rearrangement involved c-Met-mediated RhoA/ROCK signaling in glioblastoma. Thus, our study proved that paeoniflorin could inhibit migration and invasion and actin cytoskeleton rearrangement through inhibition of HGF/c-Met/RhoA/ROCK signaling in glioblastoma, suggesting that paeoniflorin might be a candidate compound to treat glioblastoma.


Assuntos
Glioblastoma/tratamento farmacológico , Glucosídeos/farmacologia , Fator de Crescimento de Hepatócito/genética , Monoterpenos/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Proteína rhoA de Ligação ao GTP/genética , Citoesqueleto de Actina/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Invasividade Neoplásica/genética , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/genética
12.
Int J Mol Sci ; 20(6)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884801

RESUMO

The small GTPase Rho and its downstream effector, Rho-kinase (ROCK), regulate various cellular functions, including organization of the actin cytoskeleton, cell adhesion and migration. A pro-inflammatory lipid mediator, lysophosphatidic acid (LPA), is a potent activator of the Rho/ROCK signalling pathway and has been shown to induce the expression of chemokines and cell adhesion molecules (CAMs). In the present study, we aimed to elucidate the precise mechanism by which ROCK regulates LPA-induced expressions and functions of chemokines and CAMs. We observed that ROCK blockade reduced LPA-induced phosphorylation of IκBα and inhibited NF-κB RelA/p65 phosphorylation, leading to attenuation of RelA/p65 nuclear translocation. Furthermore, small interfering RNA-mediated ROCK isoform knockdown experiments revealed that LPA induces the expression of monocyte chemoattractant protein-1 (MCP-1) and E-selectin via ROCK2 in human aortic endothelial cells (HAECs). Importantly, we found that ROCK2 but not ROCK1 controls LPA-induced monocytic migration and monocyte adhesion toward endothelial cells. These findings demonstrate that ROCK2 is a key regulator of endothelial inflammation. We conclude that targeting endothelial ROCK2 is potentially effective in attenuation of atherosclerosis.


Assuntos
Aterosclerose/genética , Células Endoteliais/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Quinases Associadas a rho/genética , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/genética , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Aorta/citologia , Aorta/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Adesão Celular/genética , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Selectina E/genética , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Quinase I-kappa B/genética , Monócitos/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/genética , Quinases Associadas a rho/metabolismo
13.
Mol Med Rep ; 19(5): 3882-3888, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30816534

RESUMO

MicroRNA­122 (miR­122) has been reported to be involved in the pathogenesis of several types of malignancies; however, its role in prostate carcinoma remains unknown. Thus, the current study aimed to investigate the functionality of miR­122 in prostate carcinoma. Clinical data of 54 patients with prostate carcinoma who were diagnosed and treated in Union Hospital (Wuhan, China) between January 2011 and January 2013 were retrospectively analyzed. The expression levels of miR­122 and Rho­associated protein kinase 2 (ROCK2) in prostate tumor and adjacent healthy tissues of patients, as well as in the serum of prostate carcinoma patients and healthy controls, were detected by reverse transcription­quantitative polymerase chain reaction. Receiver operating characteristic curve and survival curve analyses were used to examine the diagnostic and prognostic values of serum miR­122 for prostate carcinoma. In addition, miR­122 mimic was transfected into prostate carcinoma cells, and the effects on cell proliferation and ROCK2 expression were explored by Cell Counting Kit­8 and western blot assays, respectively. It was observed that miR­122 was downregulated and ROCK2 was upregulated in tumor tissues as compared with their levels in adjacent healthy tissues. miR­122 level in the serum was also markedly lower in prostate carcinoma patients in comparison with that in healthy controls. Furthermore, a low serum level of miR­122 was found to effectively distinguish the prostate carcinoma patients from healthy controls and to be an indicator of poor survival. In prostate carcinoma cells, miR­122 overexpression inhibited the proliferation and the expression of ROCK2. Taken together, miR­122 may inhibit the proliferation of prostate carcinoma cells possibly by downregulating ROCK2 expression.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias da Próstata/patologia , Quinases Associadas a rho/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Células Tumorais Cultivadas , Quinases Associadas a rho/genética
14.
Int J Cardiol ; 281: 90-98, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30728103

RESUMO

BACKGROUND: Diabetes is associated with an increased risk of heart failure, cardiac arrhythmias and sudden cardiac death. We previously showed that ROCK2 expression is elevated in diabetic rat hearts, and that ROCK inhibition acutely improves their contractile function. In the present study we investigated whether inhibition of ROCK or partial deletion of ROCK2 improves impaired Ca2+ handling in the diabetic heart. METHODS: Contractile properties and Ca2+ transients were measured before and after treatment with the ROCK inhibitor Y-27632 (1 µM) in fluo-4-loaded cardiomyocytes isolated from streptozotocin (STZ)-diabetic or non-diabetic rats. Cardiac function was determined in vivo, and contractile properties and Ca2+ transients also measured in cardiomyocytes from non-diabetic and STZ-diabetic wild-type (WT) and ROCK2+/- mice. RESULTS: ROCK inhibition improved some parameters of contractile function and Ca2+ handling in cardiomyocytes from diabetic rat hearts. In addition, ROCK inhibition attenuated the diabetes-induced delayed aftercontractions (DACs) and associated irregular Ca2+ transients induced by increased [Ca2+]o. Although no overt cardiac dysfunction was detected in diabetic WT mice, cardiomyocytes from these mice also developed arrhythmic Ca2+ transients in response to increased [Ca2+]. These were attenuated in cardiomyocytes from diabetic ROCK2+/- mice, in association with decreased diastolic Ca2+ leak and with reduction of the diabetes-induced increased phosphorylation of both CaMKII and the ryanodine receptor (RyR). CONCLUSIONS: These data suggest that ROCK2 contributes to diabetes-induced impaired cardiac Ca2+ homeostasis, at least in part by promoting CaMKII-mediated phosphorylation of RyR. This may have important clinical implications for the treatment of the increased incidence of dysrhythmias in diabetes.


Assuntos
Arritmias Cardíacas/metabolismo , Cálcio/metabolismo , Diabetes Mellitus Experimental/metabolismo , Miócitos Cardíacos/metabolismo , Quinases Associadas a rho/metabolismo , Amidas/farmacologia , Animais , Arritmias Cardíacas/genética , Células Cultivadas , Diabetes Mellitus Experimental/genética , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , Fosforilação/fisiologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Quinases Associadas a rho/genética
15.
J Physiol Biochem ; 75(1): 19-28, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30729392

RESUMO

Diabetes mellitus significantly hampers the development of cardioprotective response to remote pre/post/perconditioning stimuli by impairing the activation of cardioprotective signaling pathways. Among the different pathways, the impairment in O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling and release of cardioprotective humoral factor may contribute in attenuating remote preconditioning-induced cardioprotection. Moreover, the failure to phosphorylate extracellular signal related kinase (ERK), phosphoinositide-3-kinase (PI3K), and AKT along with up-regulation of mechanistic target of rapamycin (mTOR) and decrease in autophagy may also attenuate remote preconditioning-induced cardioprotection. Remote perconditioning stimulus also fails to phosphorylate AKT kinase in diabetic heart. In addition, diabetes may increase the oxidative stress, reactive oxygen species (ROS) production, decrease the beclin expression, and inhibit autophagy to attenuate remote perconditioning-induced cardioprotection. Moreover, diabetes-induced increase in the Rho-associated kinase (ROCK) activity, decrease in the arginase activity, and reduction in nitric oxide (NO) bioavailability may also contribute in decreasing remote perconditioning-induced cardioprotection. Diabetes may reduce the phosphorylation of adenosine 5'-monophosphate activated protein kinase (AMPKα) and increase the phosphorylation of mTOR to attenuate cardioprotection of remote postconditioning. The present review describes the role of diabetes in attenuating remote ischemic conditioning-induced cardioprotection along with the possible mechanisms.


Assuntos
Acetilglucosamina/metabolismo , Diabetes Mellitus Tipo 2/genética , Regulação da Expressão Gênica , Precondicionamento Isquêmico Miocárdico , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/terapia , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Arginase/genética , Arginase/metabolismo , Autofagia , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Óxido Nítrico/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
16.
Nano Lett ; 19(3): 1963-1975, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30740982

RESUMO

Material implants trigger host reactions generated by cells, such as macrophages, which display dynamic adhesion and polarization including M1 inflammatory state and M2 anti-inflammatory state. Creating materials that enable diverse nanoscale display of integrin-binding groups, such as RGD ligand, can unravel nanoscale recruitment and ligation of integrin, which modulate cellular adhesion and activation. Here, we synthesized gold nanorods (GNRs) with various nanoscale anisotropies (i.e., aspect ratios, ARs), but in similar surface areas, and controlled their substrate conjugation to display an anisotropic ligand nanogeometry without modulating ligand density. Using nanoscale immunolabeling, we demonstrated that highly anisotropic ligand-coated GNRs ("AR4" and "AR7") facilitated the recruitment of integrin ß1 on macrophages to their nanoscale surfaces. Consequently, highly anisotropic GNRs (e.g., "AR4" and "AR7") elevated the adhesion and M2 state of macrophages, with the inhibition of their M1 state in the culture and mice, entailing rho-associated protein kinase. This nanoscale anisotropic nanogeometry provides a novel and critical parameter to be considered in the generation of biomaterials to potentially modulate host reactions to the implants for immunomodulatory tissue regeneration.


Assuntos
Integrina beta1/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas/química , Próteses e Implantes , Animais , Anisotropia , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/química , Adesão Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Integrina beta1/química , Ligantes , Macrófagos/química , Camundongos , Nanopartículas/administração & dosagem , Nanotubos/química , Oligopeptídeos/química , Quinases Associadas a rho/genética
17.
Reprod Biol ; 19(1): 45-54, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30704840

RESUMO

The aim of this study was to investigate the expression of RhoA/Rho-kinase in the uterus and the effect of Rho-kinase inhibitors on uterine contractions of dehydroepiandrosterone (DHEA) induced polycystic ovary syndrome (PCOS) rats. Forty-four female Sprague-Dawley (21 days old) rats divided into three groups: The control group (n = 14, any procedure was not performed), vehicle group (n = 14, 0.2 ml of sesame oil, subcutaneous injection, 20 days) and PCOS group (n = 16, DHEA 6 mg/100 g in 0.2 ml of sesame oil, subcutaneous injection, 20 days). The myometrium thickness and uterine wet weight were assessed. The mRNA and protein expressions of Rho A, the effect of Rho-kinase inhibitors (fasudil and Y-27632) on KCl, carbachol, and PGF2α induced contractions were evaluated in the uterus. In the PCOS group, the myometrium thickness and uterine wet weight significantly increased compared to the control group and vehicle group. The mRNA expression level and the immunoreactive score of Rho A, ROCK 1, ROCK 2 were similar in all groups. In the PCOS group, KCl, carbachol, and PGF2α induced uterine contractions significantly increased compared to the control group and vehicle group. Fasudil and Y-27632 significantly inhibited KCl, carbachol, and PGF2α induced uterine contractions in all groups. In conclusion, the expression of Rho A, ROCK 1, ROCK 2 not changed although myometrium thickness, uterine wet weight and the contractile responses of uterus increased in the PCOS group. The results suggest that the Rho-kinase inhibitors effectively suppressed increased contractions in the PCOS group they might be potential therapeutic agents.


Assuntos
Regulação Enzimológica da Expressão Gênica/fisiologia , Síndrome do Ovário Policístico/metabolismo , Útero/metabolismo , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Imuno-Histoquímica , Miométrio/efeitos dos fármacos , Ovário/efeitos dos fármacos , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Esfregaço Vaginal , Proteínas rho de Ligação ao GTP/genética , Quinases Associadas a rho/genética
18.
J Cardiothorac Surg ; 14(1): 22, 2019 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683137

RESUMO

BACKGROUND: Grafting vessel with LIMA to the left anterior descending coronary artery plays a most important role in the long-term prognosis of OPCABG surgery. The aim of this study was to compare the effects of isoflurane preconditioning on miRs and mRNAs levels in the left internal mammary arterie (LIMA) graft with propofol in patients undergoing off-pump coronary artery bypass surgery (OPCABG). METHODS: Patients were randomly assigned to receive either propofol (n = 15), or interrupted isoflurane (n = 15). In group P, propofol administration was continued at 3-5 mg/kg/h intravenous injection for the duration of surgery. Five minutes prior to incision, patients of the isoflurane group (group Iso) received 2 cycles of 1 MAC isoflurane. RESULTS: miR-221 were significantly lower in group Iso (P < 0 .05). E-selectin mRNA, RhoA mRNA and ROK mRNA were significantly lower at specimens of LIMA in group Iso compared with those in group P patients (P < 0 .05). The expression of NOS3 mRNA was significantly higher in group Iso patients (P < 0 .05). CONCLUSION: Our findings provide some insight that prior interrupted isoflurane administration could regulate miR-221, and downstream effectors (mRNAs) and resulted in actual attenuation of inflammation and spasm of LIMA in patients undergoing OPCABG surgery. TRIAL REGISTRATION: NCT No. ( ClinicalTrials.gov ): NCT02678650; Registration date: January 23, 2016.


Assuntos
Ponte de Artéria Coronária sem Circulação Extracorpórea/métodos , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/metabolismo , Precondicionamento Isquêmico Miocárdico/métodos , Isoflurano/farmacologia , Óxido Nítrico/genética , Quinases Associadas a rho/genética , Idoso , Anestésicos Inalatórios/farmacologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Artéria Torácica Interna/metabolismo , Pessoa de Meia-Idade , Óxido Nítrico/biossíntese , Estudos Prospectivos , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Quinases Associadas a rho/biossíntese
19.
Cell Mol Life Sci ; 76(6): 1169-1183, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30599068

RESUMO

Senescent cells undergo structural and functional changes that affect essentially every aspect of cell physiology. To date, the impact of senescence on the cytoskeleton is poorly understood. This study evaluated the cytoskeleton in two independent cellular models of kidney epithelium senescence. Our work identified multiple senescence-related alterations that impact microtubules and filamentous actin during interphase. Both filamentous systems reorganized profoundly when cells became senescent. As such, microtubule stability increased during senescence, making these filaments more resistant to disassembly in the cold or by nocodazole. Microtubule stabilization was accompanied by enhanced α-tubulin acetylation on lysine 40 and the depletion of HDAC6, the major deacetylase for α-tubulin lysine 40. Rho-associated kinase Rock1 is an upstream regulator that modulates key properties of the cytoplasmic cytoskeleton. Our research shows that Rock1 concentrations were reduced significantly in senescent cells, and we revealed a mechanistic link between microtubule stabilization and Rock1 depletion. Thus, Rock1 overexpression partially restored the cold sensitivity of microtubules in cells undergoing senescence. Additional components relevant to microtubules were affected by senescence. Specifically, we uncovered the senescence-related loss of the microtubule nucleating protein γ-tubulin and aberrant formation of γ-tubulin foci. Concomitant with the alterations of microtubule and actin filaments, senescent cells displayed functional changes. In particular, cell migration was impaired significantly in senescent cells. Taken together, our study identified new senescence-associated deficiencies of the microtubule and actin cytoskeleton, provided insights into the underlying molecular mechanisms and demonstrated functional consequences that are important to the physiology and function of renal epithelial cells.


Assuntos
Citoesqueleto de Actina/metabolismo , Senescência Celular , Microtúbulos/metabolismo , Tubulina (Proteína)/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Animais , Linhagem Celular , Células Epiteliais/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Túbulos Renais Proximais/citologia , Microscopia Confocal , Microtúbulos/efeitos dos fármacos , Nocodazol/farmacologia , Suínos , Moduladores de Tubulina/farmacologia , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
20.
Drug Des Devel Ther ; 13: 285-290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30666090

RESUMO

Aim: To testify the hypothesis that endostatin exerts antifibrotic effects in hepatic stellate cells (HSCs) by modulating RhoA (ras homolog gene family, member A)/ROCK 1 (Rho-associated protein kinase 1) signal pathways. Materials and methods: HSCs-T6 of passages 3-5 were cultured in DMEM and serum starved for 48 hours. HSCs were grouped as follows: control group, TGF-ß1 (transforming growth factor ß1) group, endostatin+TGF-ß1 group, PDGF-BB (platelet-derived growth factor-BB) group, and endostatin+PDGF-BB group. In the PDGF-BB group, HSCs were treated with PDGF-BB (200 ng/mL) for 72 hours; in the TGF-ß1 group, they were treated with TGF-ß1 (10 ng/mL) for 72 hours. In the Endostatin+TGF-ß1 group or Endostatin+PDGF-BB group, HSCs were treated with TGF-ß1 (10 ng/mL) or PDGF-BB (200 ng/mL) for 72 hours after pretreatment with endostatin (5 µg/mL) for 1 hour. In the control group, HSCs were only treated with serum-free DMEM for 72 hours. Collagen I was analyzed with ELISA. F-actin was detected with immunofluorescent staining. The mRNAs and proteins of α-smooth muscle actin, RhoA, and ROCK1 were analyzed by using real-time PCR and Western blot, respectively. Results: TGF-ß1 and PDGF-BB promote the proliferation of HSCs significantly at 48 and 72 hours. Endostatin inhibits the proliferation effect induced by TGF-ß1 or PDGF-BB significantly (P<0.01). The expression of collagen I and F-actin was significantly upregulated in both TGF-ß1 and PDGF-BB groups than in the control group (P<0.01). Both the collagen I and F-actin expression were downregulated significantly in the endostatin-treated groups (P<0.05). Endostatin significantly inhibited the upregulated expression of α-smooth muscle actin, RhoA, and ROCK1 induced by TGF-ß1 or PDGF-BB (P<0.01). Conclusion: These results suggested that endostatin inhibited TGF-ß1- or PDGF-BB-induced fibrosis in HSCs by modulating RhoA/ROCK signal pathways.


Assuntos
Antineoplásicos/farmacologia , Becaplermina/antagonistas & inibidores , Endostatinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Quinases Associadas a rho/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Animais , Becaplermina/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Ratos , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
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