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1.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525359

RESUMO

Nonalcoholic fatty liver disease is defined as the accumulation of excessive fat in the liver in the absence of excessive alcohol consumption or any secondary cause. Although the disease generally remains asymptomatic, chronic liver inflammation leads to fibrosis, liver cirrhosis, and even to the development of hepatocellular carcinoma (HCC). Fibrosis results from epithelial-mesenchymal transition (EMT), which leads to dedifferentiation of epithelial cells into cells with a mesenchymal-like phenotype. During EMT, epithelial cells with high expression of E-cadherin, influenced by growth factors, cytokines, and inflammatory processes, undergo morphological changes via enhanced expression of, e.g., vimentin, fibronectin, and N-cadherin. An inducer of EMT and, consequently, of fibrosis development is transforming growth factor beta (TGFß), a pleiotropic cytokine associated with the progression of hepatocarcinogenesis. However, the understanding of the molecular events that direct the development of steatosis into steatohepatitis and liver fibrosis remains incomplete. Our study revealed that both prolonged exposure of hepatocarcinoma cells to fatty acids in vitro and high-fat diet in mice (20 weeks) result in inflammation. Prolonged treatment with fatty acids increased the levels of TGFß, MMP9, and ß-catenin, important EMT inducers. Moreover, the livers of mice fed a high-fat diet exhibited features of liver fibrosis with increased TGFß and IL-1 levels. Increased expression of IL-1 correlated with a decrease in monocyte chemoattractant protein-induced protein 1 (MCPIP1), a negative regulator of the inflammatory response that regulates the stability of proinflammatory transcripts encoding IL-1. Our study showed that a high-fat diet induced EMT by increasing the levels of EMT-activating transcription factors, including Zeb1, Zeb2, and Snail and changed the protein profile to a profile characteristic of the mesenchymal phenotype.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/genética , Fator de Crescimento Transformador beta/genética , beta Catenina/genética , Animais , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ácido Oleico/farmacologia , Ribonucleases/genética , Ribonucleases/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/agonistas , Fator de Crescimento Transformador beta/metabolismo , Vimentina/genética , Vimentina/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , beta Catenina/agonistas , beta Catenina/metabolismo
2.
Angiogenesis ; 20(3): 325-340, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28197812

RESUMO

Monocyte Chemoattractant protein-induced protein 1 (MCPIP1), also known as Regnase-1, is encoded by the ZC3H12a gene, and it mediates inflammatory processes by regulating the stability of transcripts coding for proinflammatory cytokines and controlling activity of transcription factors, such as NF-κB and AP1. We found that MCPIP1 transcript and protein levels are strongly downregulated in clear cell renal cell carcinoma (ccRCC) samples, which were derived from patients surgically treated for renal cancer compared to surrounded normal tissues. Using Caki-1 cells as a model, we analyzed the role of MCPIP1 in cancer development. We showed that MCPIP1 expression depends on the proteasome activity; however, hypoxia and hypoxia inducible factor 2 alfa (HIF2α) are key factors lowering MCPIP1 expression. Furthermore, we found that MCPIP1 negatively regulates HIF1α and HIF2α levels and in the case of the last one, the mechanism is based on the regulation of the half time of transcript coding for HIF2α. Enhanced expression of MCPIP1 in Caki-1 cells results in a downregulation of transcripts encoding VEGFA, GLUT1, and IL-6. Furthermore, MCPIP1 decreases the activity of mTOR and protein kinase B (Akt) in normoxic conditions. Taken together, MCPIP1 contributes to the ccRCC development.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Transportador de Glucose Tipo 1/metabolismo , Humanos , Leupeptinas/farmacologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Inibidores de Proteassoma/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonucleases/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Hepatol Commun ; 7(3): e0008, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36809310

RESUMO

BACKGROUND AND AIMS: NAFLD is characterized by the excessive accumulation of fat in hepatocytes. NAFLD can range from simple steatosis to the aggressive form called NASH, which is characterized by both fatty liver and liver inflammation. Without proper treatment, NAFLD may further progress to life-threatening complications, such as fibrosis, cirrhosis, or liver failure. Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through the cleavage of transcripts coding for proinflammatory cytokines and the inhibition of NF-κB activity. METHODS: In this study, we investigated MCPIP1 expression in the liver and peripheral blood mononuclear cells (PBMCs) collected from a cohort of 36 control and NAFLD patients hospitalized due to bariatric surgery or primary inguinal hernia laparoscopic repair. Based on liver histology data (hematoxylin and eosin and Oil Red-O staining), 12 patients were classified into the NAFL group, 19 into the NASH group, and 5 into the control (non-NAFLD) group. Biochemical characterization of patient plasma was followed by expression analysis of genes regulating inflammation and lipid metabolism. The MCPIP1 protein level was reduced in the livers of NAFL and NASH patients in comparison to non-NAFLD control individuals. In addition, in all groups of patients, immunohistochemical staining showed that the expression of MCPIP1 was higher in the portal fields and bile ducts in comparison to the liver parenchyma and central vein. The liver MCPIP1 protein level negatively correlated with hepatic steatosis but not with patient body mass index or any other analyte. The MCPIP1 level in PBMCs did not differ between NAFLD patients and control patients. Similarly, in patients' PBMCs there were no differences in the expression of genes regulating ß-oxidation (ACOX1, CPT1A, and ACC1) and inflammation (TNF, IL1B, IL6, IL8, IL10, and CCL2), or transcription factors controlling metabolism (FAS, LCN2, CEBPB, SREBP1, PPARA, and PPARG). CONCLUSION: We have demonstrated that MCPIP1 protein levels are reduced in NAFLD patients, but further research is needed to investigate the specific role of MCPIP1 in NAFL initiation and the transition to NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Inflamação , Cirrose Hepática/patologia
4.
Eur J Pharmacol ; 922: 174804, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35257717

RESUMO

Metastasis is responsible for as many as 90% of cancer-associated deaths in patients. The metastatic process is a result of tumor cell migration and invasion associated with morphological changes and increased expression of several genes involved in cell migration. We have already shown that monocyte chemotactic protein-1-induced protein-1 (MCPIP1), a negative regulator of inflammatory processes, influences cell morphology, prevents the epithelial to mesenchymal transition program, and regulates metastasis in clear cell renal cell carcinoma (ccRCC). However, the mechanism by which MCPIP1 influences cell migratory potential is unknown. In this study, we investigated how MCPIP1 affects ccRCC cell migration. We showed that MCPIP1 prevents morphological transformation and drastically reduces the migration of ccRCC cells. MCPIP1 decreases the levels of Rho GTPases and reduces the phosphorylation of FAK at Tyr-397 and Tyr-861 and Src at Tyr-418. The loss of MCPIP1 RNase activity results in actin remodeling, an increase in the levels of Rho proteins and the phosphorylation of FAK on Tyr-397, which leads to Tyr-418 Src phosphorylation and an increase in migration activity. Moreover, we observed increased expression of IL-1ß in ccRCC cells and tumors lacking MCPIP1 RNase activity. Additionally, microarray analysis of tissues from patients with ccRCC revealed changes in the expression of several genes correlated with migration as tumor progression occurred. This study indicates an important role of MCPIP1 as a regulator of migratory potential in ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Quimiocina CCL2/metabolismo , Transição Epitelial-Mesenquimal/genética , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Neoplasias Renais/patologia , Ribonucleases/genética , Proteínas rho de Ligação ao GTP/metabolismo
5.
Cell Death Dis ; 13(9): 814, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36138026

RESUMO

Tyrosine kinase inhibitors (TKIs) are the most commonly used targeted therapeutics in clear-cell renal cell carcinoma (ccRCC); however, drug resistance limits their utility and can lead to tumor "flare-up" and progression. In this study, we show that RCC resistance to sunitinib and sorafenib involves different mechanisms and leads to increased malignancy. Sunitinib decreased tumor growth and cell motility along with increased E-cadherin expression and secretion of the proangiogenic cytokines IL6 and IL8, which activated senescence in ccRCC cells and led to VE-cadherin phosphorylation, enhancing tumor angiogenesis. Sorafenib resistance increased the levels of mesenchymal markers and the secretion of MMP9, which cleaved VE-cadherin and disrupted endothelial cell integrity. Both sunitinib resistance and sorafenib resistance led to activation of the c-Met receptor IRAK1 and downregulation of the tumor suppressor MCPIP1, resulting in an increase in the metastasis of resistant cells, possibly due in part to enhanced vascularization of ccRCC. MCPIP1 overexpression partially overcame resistance to these drugs by decreasing micrometastasis and decreasing the expression of factors involved in tumorigenesis. In tumor samples from ccRCC patients, we observed a significant increase in the level of the c-Met receptor, IRAK1 and a decrease in MCPIP1 with respect to normal kidney tissue. Our results indicate separate novel mechanisms for sunitinib and sorafenib resistance, which both lead to MCPIP1 inhibition and ccRCC progression. The presented study suggests caution in the treatment of RCC with TKIs, which may lead to the unintended outcome of tumor progression.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Proteínas Proto-Oncogênicas c-met , Ribonucleases , Fatores de Transcrição , Caderinas/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Rim/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neovascularização Patológica/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Ribonucleases/genética , Ribonucleases/metabolismo , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
Oncogene ; 40(50): 6720-6735, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34657130

RESUMO

Epithelial-mesenchymal transition (EMT) refers to the acquisition of mesenchymal properties in cells participating in tumor progression. One hallmark of EMT is the increased level of active ß-catenin, which can trigger the transcription of Wnt-specific genes responsible for the control of cell fate. We investigated how Monocyte Chemotactic Protein-1-Induced Protein-1 (MCPIP1), a negative regulator of inflammatory processes, affects EMT in a clear cell renal cell carcinoma (ccRCC) cell line, patient tumor tissues and a xenotransplant model. We showed that MCPIP1 degrades miRNAs via its RNase activity and thus protects the mRNA transcripts of negative regulators of the Wnt/ß-catenin pathway from degradation, which in turn prevents EMT. Mechanistically, the loss of MCPIP1 RNase activity led to the upregulation of miRNA-519a-3p, miRNA-519b-3p, and miRNA-520c-3p, which inhibited the expression of Wnt pathway inhibitors (SFRP4, KREMEN1, CXXC4, CSNK1A1 and ZNFR3). Thus, the level of active nuclear ß-catenin was increased, leading to increased levels of EMT inducers (SNAI1, SNAI2, ZEB1 and TWIST) and, consequently, decreased expression of E-cadherin, increased expression of mesenchymal markers, and acquisition of the mesenchymal phenotype. This study revealed that MCPIP1 may act as a tumor suppressor that prevents EMT by stabilizing Wnt inhibitors and decreasing the levels of active ß-catenin and EMT inducers.


Assuntos
Carcinoma de Células Renais/patologia , Transição Epitelial-Mesenquimal , Fatores de Transcrição Forkhead/fisiologia , MicroRNAs/antagonistas & inibidores , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo , Proteína Wnt1/antagonistas & inibidores , beta Catenina/antagonistas & inibidores , Animais , Apoptose , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Ribonucleases/genética , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
7.
Biochim Biophys Acta Mol Basis Dis ; 1867(5): 166086, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33513427

RESUMO

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by progressive destruction of the intrahepatic bile ducts. The immunopathology of PBC involves excessive inflammation; therefore, negative regulators of inflammatory response, such as Monocyte Chemoattractant Protein-1-Induced Protein-1 (MCPIP1) may play important roles in the development of PBC. The aim of this work was to verify whether Mcpip1 expression protects against development of PBC. Genetic deletion of Zc3h12a was used to characterize the role of Mcpip1 in the pathogenesis of PBC in 6-52-week-old mice. We found that Mcpip1 deficiency in the liver (Mcpip1fl/flAlbCre) recapitulates most of the features of human PBC, in contrast to mice with Mcpip1 deficiency in myeloid cells (Mcpip1fl/flLysMCre mice), which present with robust myeloid cell-driven systemic inflammation. In Mcpip1fl/flAlbCre livers, intrahepatic bile ducts displayed proliferative changes with inflammatory infiltration, bile duct destruction, and fibrosis leading to cholestasis. In plasma, increased concentrations of IgG, IgM, and AMA autoantibodies (anti-PDC-E2) were detected. Interestingly, the phenotype of Mcpip1fl/flAlbCre mice was robust in 6-week-old, but milder in 12-24-week-old mice. Hepatic transcriptome analysis of 6-week-old and 24-week-old Mcpip1fl/flAlbCre mice showed 812 and 8 differentially expressed genes, respectively, compared with age-matched control mice, and revealed a distinct set of genes compared to those previously associated with development of PBC. In conclusion, Mcpip1fl/flAlbCre mice display early postnatal phenotype that recapitulates most of the features of human PBC.


Assuntos
Autoanticorpos/imunologia , Imunoglobulinas/imunologia , Inflamação/patologia , Cirrose Hepática Biliar/patologia , Cirrose Hepática/patologia , Fenótipo , Ribonucleases/fisiologia , Animais , Feminino , Inflamação/etiologia , Inflamação/metabolismo , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Cirrose Hepática Biliar/etiologia , Cirrose Hepática Biliar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
8.
Pharmacol Rep ; 72(1): 1-12, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32016853

RESUMO

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Globally, it is currently the most common liver disease and is estimated to affect up to 25% of the population. In the first stage, NAFLD is characterized by simple hepatic steatosis (NAFL, nonalcoholic fatty liver) that might progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular carcinoma. In this review, we discuss the global burden of NAFLD, together with future perspectives on how this epidemic could be restrained. There is also an urgent need for the development of new medical strategies for NAFLD patients. We aim to present the beneficial effects of life-style modifications that should be advised to both non-obese and obese NAFLD patients. Since there are currently no medications directly used for the treatment of more advanced NAFLD stages, the central part of this review summarizes ongoing and recently completed clinical trials testing promising drugs for NASH resolution. The marketing of new therapeutic agents would greatly increase the odds of reducing the global burden of NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/complicações , Animais , Carcinoma Hepatocelular/etiologia , Progressão da Doença , Humanos , Estilo de Vida , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Prevalência
9.
Eur J Pharmacol ; 888: 173591, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32971087

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer. It is highly vascularized and largely resistant to traditional chemo- and radiotherapy. Decreases in tumour suppressors and low levels of the anti-inflammatory Monocyte Chemoattractant Protein-Induced Protein 1 (MCPIP1) play important roles in the development and progression of ccRCC. MCPIP1, also called Regnase-1, possesses endonuclease activity and degrades the mRNA of proinflammatory cytokines such as IL-6, IL-1ß, IL-12 and IL-2. We previously showed that the level of MCPIP1 decreases with ccRCC progression. In this study, we explored the role of MCPIP1 in regulating the levels of tumour suppressors. We found low levels of the suppressors PTEN, RECK and TIMP3 and high levels of MMPs in patients with ccRCC who had already been shown to have low MCPIP1 expression. We demonstrated that MCPIP1 regulates the expression levels of PTEN, RECK and TIMP3 in ccRCC cell lines as well as in vivo models of ccRCC. MCPIP1 overexpression increased the expression of tumour suppressors. Moreover, we observed that the RNase activity of MCPIP1 is responsible for the modulation of apoptosis and activation of prometastatic signalling pathways. Furthermore, we found a negative correlation between high levels of IL6, a direct target of MCPIP1 RNase activity, and TIMP3 in patients, indicating that MCPIP1 and TIMP3 might collectively cause the high levels of IL6 in ccRCC patients. Taken together, our results show the importance of MCPIP1 in regulating the level of tumour suppressors and, consequently, in ccRCC development and progression.


Assuntos
Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/prevenção & controle , Ribonucleases/biossíntese , Fatores de Transcrição/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Ribonucleases/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
10.
Cancer Res ; 67(5): 2131-40, 2007 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-17332343

RESUMO

Rhabdomyosarcoma frequently infiltrates bone marrow and this process involves the stromal-derived factor-1 (SDF-1)-CXCR4 axis. Because leukemia inhibitory factor (LIF), like SDF-1, is secreted by bone marrow stroma and directs the regeneration of skeletal muscles, we examined whether the LIF-LIF receptor (LIF-R) axis affects the biology of rhabdomyosarcoma cells. We found that in rhabdomyosarcoma cells, LIF stimulates the following: (a) phosphorylation of mitogen-activated protein kinase p42/44, AKT, and signal transducers and activators of transcription 3, (b) adhesion and chemotaxis, and (c) increased resistance to cytostatics. To compare the biological effects of LIF versus SDF-1, we examined the RH30 cell line, which is highly responsive to both ligands, and found that the chemotaxis of these cells is significantly reduced when the inhibitors of both receptors (T140 for CXCR4 and gp190 blocking antibody for LIF-R) are added simultaneously. Subsequently, by using repetitive chemotaxis to LIF or SDF-1, we selected from the RH30 line subpopulations of cells that respond to LIF but not SDF-1 (RH30-L) or to SDF-1 but not LIF (RH30-S). We found that (a) RH30-L cells seed better to the bone marrow, liver, and lymph nodes of immunodeficient mice than RH30-S cells and (b) mice inoculated i.m. with the RH30-L cells had more rhabdomyosarcoma cells in the bone marrow and lung after 6 weeks. Thus, we present the first evidence that the LIF-LIF-R axis may direct rhabdomyosarcoma metastasis. Further, because we showed that the in vivo metastasis of RH30 cells is inhibited by small interfering RNA against LIF-R, molecular targeting of this axis could become a new strategy to control the metastasis of rhabdomyosarcoma.


Assuntos
Fator Inibidor de Leucemia/fisiologia , Rabdomiossarcoma/patologia , Animais , Células da Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Humanos , Fator Inibidor de Leucemia/metabolismo , Fator Inibidor de Leucemia/farmacologia , Camundongos , Camundongos SCID , Metástase Neoplásica , Transplante de Neoplasias , Oncostatina M/metabolismo , Oncostatina M/farmacologia , Receptores de OSM-LIF/metabolismo , Rabdomiossarcoma/metabolismo
11.
J Exp Clin Cancer Res ; 38(1): 421, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31639017

RESUMO

The monocyte chemoattractant protein-induced protein (MCPIP) family consists of 4 members (MCPIP1-4) encoded by the ZC3h12A-D genes, which are located at different loci. The common features of MCPIP proteins are the zinc finger domain, consisting of three cysteines and one histidine (CCCH), and the N-terminal domain of the PilT protein (PilT-N-terminal domain (PIN domain)). All family members act as endonucleases controlling the half-life of mRNA and microRNA (miRNA). The best-studied member of this family is MCPIP1 (also known as Regnase-1).In this review, we discuss the current knowledge on the role of MCPIP1 in cancer-related processes. Because the characteristics of MCPIP1 as a fundamental negative regulator of immune processes have been comprehensively described in numerous studies, we focus on the function of MCPIP1 in modulating apoptosis, angiogenesis and metastasis.


Assuntos
MicroRNAs/metabolismo , Neoplasias/genética , Ribonucleases/genética , Fatores de Transcrição/genética , Apoptose , Proliferação de Células , Humanos
12.
Cells ; 8(3)2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909397

RESUMO

C-Met tyrosine kinase receptor plays an important role under normal and pathological conditions. In tumor cells' overexpression or incorrect activation of c-Met, this leads to stimulation of proliferation, survival and increase of motile activity. This receptor is also described as a marker of cancer initiating cells. The latest research shows that the c-Met receptor has an influence on the development of resistance to targeted cancer treatment. High c-Met expression and activation in renal cell carcinomas is associated with the progression of the disease and poor survival of patients. C-Met receptor has become a therapeutic target in kidney cancer. However, the therapies used so far using c-Met tyrosine kinase inhibitors demonstrate resistance to treatment. On the other hand, the c-Met pathway may act as an alternative target pathway in tumors that are resistant to other therapies. Combination treatment together with c-Met inhibitor reduces tumor growth, vascularization and pro-metastatic behavior and results in suppressed mesenchymal phenotype and vascular endothelial growth factor (VEGF) secretion. Recently, it has been shown that the acquirement of mesenchymal phenotype or lack of cell differentiation might be related to the presence of the c-Met receptor and is consequently responsible for therapy resistance. This review presents the results from recent studies identifying c-Met as an important factor in renal carcinomas being responsible for tumor growth, progression and metastasis, indicating the role of c-Met in resistance to antitumor therapy and demonstrating the pivotal role of c-Met in supporting mesenchymal cell phenotype.


Assuntos
Diferenciação Celular , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Transição Epitelial-Mesenquimal , Humanos , Neoplasias Renais/metabolismo , Fenótipo
13.
Int J Oncol ; 33(2): 309-15, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18636151

RESUMO

Connexins and gap junctions play a crucial role during carcinogenesis. While diverse regulatory systems have been shown to modulate their function, the influence of cell motility on the intensity of gap junctional intercellular coupling has yet to be systematically addressed. Since cancer cell motility and intercellular coupling determine cancer development, we aimed at elucidating how mutual cell translocation modulates the intensity of gap junctional coupling in cell populations. Time-lapse analyses of the motility of connexin43 (Cx43)-coupled rat prostate carcinoma (MAT-LyLu) and mouse melanoma (B16) cells cultured on hyper-adhesive substrata revealed a reduced intensity of intercellular translocations in the two cell populations compared to the control conditions. While no detectable effects on the architecture of the actin cytoskeleton and Cx43 expression and phosphorylation were observed, the inhibition of cell motility was paralleled by an increase in the abundance of Cx43-positive plaques in cell-to-cell contacts and an enhancement of gap junctional coupling in cell populations cultured on hyper-adhesive substrata. Thus, a direct correlation between two cellular parameters crucial for carcinogenesis, i.e. cell motility and gap junctional coupling intensity exists in cancer cell populations.


Assuntos
Comunicação Celular/fisiologia , Movimento Celular/fisiologia , Junções Comunicantes/fisiologia , Melanoma Experimental/patologia , Neoplasias da Próstata/patologia , Animais , Linhagem Celular Tumoral , Conexina 43/metabolismo , Immunoblotting , Masculino , Melanoma Experimental/metabolismo , Camundongos , Microscopia de Fluorescência , Neoplasias da Próstata/metabolismo , Ratos
14.
Oncotarget ; 9(9): 8597-8613, 2018 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-29492220

RESUMO

We used RNA sequencing (RNA-Seq) technology to investigate changes in the transcriptome profile in the Caki-1 clear cell renal cell carcinoma (ccRCC) cells, which overexpress monocyte chemoattractant protein-induced protein 1 (MCPIP1). RNA-Seq data showed changes in 11.6% and 41.8% of the global transcriptome of Caki-1 cells overexpressing wild-type MCPIP1 or its D141N mutant, respectively. Gene ontology and KEGG pathway functional analyses showed that these transcripts encoded proteins involved in cell cycle progression, protein folding in the endoplasmic reticulum, hypoxia response and cell signalling. We identified 219 downregulated transcripts in MCPIP1-expressing cells that were either unchanged or upregulated in D141N-expressing cells. We validated downregulation of 15 transcripts belonging to different functional pathways by qRT-PCR. The growth and viability of MCPIP1-expressing cells was reduced because of elevated p21Cip1 levels. MCPIP1-expressing cells also showed reduced levels of DDB1 transcript that encodes component of the E3 ubiquitin ligase that degrades p21Cip1. These results demonstrate that MCPIP1 influences the growth and viability of ccRCC cells by increasing or decreasing the transcript levels for proteins involved in cell cycle progression, protein folding, hypoxia response, and cell signaling.

15.
Cell Mol Biol Lett ; 12(3): 348-61, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17297558

RESUMO

The results of several epidemiological studies have suggested that a soybean-based diet is associated with a lower risk of prostate cancer. We investigated the effect of the soy isoflavone genistein on the proliferation and contact-stimulated migration of rat prostatic carcinoma MAT-LyLu and AT-2 cell lines. Genistein almost completely inhibited the growth of both MAT-LyLu and AT-2 cells in the concentration range from 25 to 100 muM, but the addition of 1 muM genistein to the medium significantly stimulated the proliferation of both cell lines. Additionally, at concentrations above 25 muM, genistein showed a potent cytotoxic effect. However, the central finding of this study is that at physiologically relevant concentrations (1 muM and 10 muM), genistein inhibits the motility of prostate cancer cells stimulated by homo-and heterotypic contacts. These results show that at physiological concentrations, genistein exerts an inhibitory effect on the migration of prostate cancer cells and suggest that it may be one of the factors responsible for the anti-metastatic activity of plant isoflavonoids.


Assuntos
Comunicação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Genisteína/farmacologia , Neoplasias da Próstata/patologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Masculino , Ratos
16.
Oncol Rep ; 37(2): 647-656, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27959446

RESUMO

The MET tyrosine kinase receptor plays an important role during tumor development and progression being responsible for proliferation, morphogenetic transformation, cell motility and invasiveness. High expression of the MET receptor has been shown to correlate with increased tumor growth and metastasis, poor prognosis and resistance to radiotherapy. Moreover, MET expression and activation has been shown to be associated with therapy resistance. The occurrence of resistance to targeted therapy might be related to the presence of cancer stem cells (CSCs). CSCs are a subpopulation of cells in the tumor that possess the ability of self-renewal, clonogenicity, radioresistance and self-sustained protection from apoptosis. Recently, MET has been postulated as an essential factor supporting the functional stem cell phenotype in some tumors and as a CSC factor is believed to be responsible for therapy resistance. This review presents the results from recent studies identifying MET as a potential marker of CSCs and tumor initiating cells, demonstrating pivotal role of MET in supporting stem cell phenotype and indicating the role of MET in acquiring resistance to antitumor therapy.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Células-Tronco Neoplásicas/enzimologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Fator de Células-Tronco/metabolismo , Animais , Humanos , Neoplasias/enzimologia
17.
Cancer Res ; 77(18): 4905-4920, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28716897

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and it forms highly vascularized tumors. The monocyte endoribonuclease MCPIP1 negatively regulates inflammation by degrading mRNA encoding proinflammatory cytokines, such as IL6, IL1, and IL12. MCPIP1 is also a negative regulator of NFκB and AP1 activity and it influences a broad range of miRNA activities. Here we report that MCPIP1 protein levels are decreased during renal cancer progression. In patient-derived tumors and xenografts established in NOD-SCID or nude mice, low MCPIP1 levels correlated strongly with increased proliferation, tumor outgrowth, and vascularity. MCPIP1 activity regulated secretion of VEGF, IL8, and CXCL12 leading to chemotaxis of microvascular endothelial cells, phosphorylation of VE-cadherin, and increased vascular permeability. Mechanistic investigations showed that MCPIP1 regulated ccRCC cell motility, lung metastasis, and mesenchymal phenotype by regulating key elements in the EMT signaling axis. Overall, our results illuminate how MCPIP1 serves as a key nodal point in coordinating tumor growth, angiogenesis, and metastatic spread in ccRCC. Cancer Res; 77(18); 4905-20. ©2017 AACR.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/secundário , Movimento Celular , Neoplasias Renais/patologia , Neovascularização Patológica/patologia , Ribonucleases/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Animais , Apoptose , Carcinoma de Células Renais/irrigação sanguínea , Carcinoma de Células Renais/metabolismo , Ciclo Celular , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Feminino , Humanos , Inflamação , Neoplasias Renais/irrigação sanguínea , Neoplasias Renais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Neovascularização Patológica/metabolismo , Fosforilação , Prognóstico , Ribonucleases/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Oncotarget ; 6(31): 31378-98, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26384300

RESUMO

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma, which may originate from impaired differentiation of mesenchymal stem cells (MSC). Expression of MET receptor is elevated in alveolar RMS subtype (ARMS) which is associated with worse prognosis, compared to embryonal RMS (ERMS). Forced differentiation of ARMS cells diminishes MET level and, as shown previously, MET silencing induces differentiation of ARMS. In ERMS cells introduction of TPR-MET oncogene leads to an uncontrolled overstimulation of the MET receptor downstream signaling pathways. In vivo, tumors formed by those cells in NOD-SCID mice display inhibited differentiation, enhanced proliferation, diminished apoptosis and increased infiltration of neutrophils. Consequently, tumors grow significantly faster and they display enhanced ability to metastasize to lungs and to vascularize due to elevated VEGF, MMP9 and miR-378 expression. In vitro, TPR-MET ERMS cells display enhanced migration, chemotaxis and invasion toward HGF and SDF-1. Introduction of TPR-MET into MSC increases survival and may induce expression of early myogenic factors depending on the genetic background, and it blocks terminal differentiation of skeletal myoblasts. To conclude, our results suggest that activation of MET signaling may cause defects in myogenic differentiation leading to rhabdomyosarcoma development and progression.


Assuntos
Diferenciação Celular , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/patologia , Neovascularização Patológica , Proteínas Proto-Oncogênicas c-met/metabolismo , Rabdomiossarcoma/patologia , Animais , Apoptose , Western Blotting , Células Cultivadas , Citometria de Fluxo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mioblastos/citologia , Mioblastos/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rabdomiossarcoma/genética , Rabdomiossarcoma/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Oncotarget ; 6(12): 10086-101, 2015 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-25888626

RESUMO

Cervical cancer is one of the leading causes of death among women suffering from tumors. Current treatment options are insufficient. Here, we investigated the MET receptor as a potential molecular target in advanced cervical cancer. Downregulation of MET receptor expression via RNA interference in different cervical carcinoma cell lines dramatically decreased tumor growth and forced tumor differentiation in vivo. MET receptor silencing also led to a dramatic decrease in cell size and a decrease in proliferation rate under normal and stress conditions. MET receptor downregulation also resulted in decreased cyclin D1 and c-myc levels but did not increase apoptosis. Subsequent experiments showed that downregulation of the MET receptor decreased the expression of a key regulator of the epithelial-to-mesenchymal transition, SLUG. and increased the expression of E-cadherin, a hallmark of the epithelial phenotype. Moreover, MET downregulation impairs expression and signaling of CXCR4 receptor, responsible for invasive phenotype. Taken together, our results strongly suggest that the MET receptor influences the oncogenic properties of cervical carcinoma cells in vitro and in vivo. These findings highlight a unique role of the MET receptor in cervical carcinoma cells and indicate the MET receptor as a potential therapeutic target for advanced cervical carcinoma.


Assuntos
Proteínas Proto-Oncogênicas c-met/metabolismo , Neoplasias do Colo do Útero/metabolismo , Animais , Apoptose/fisiologia , Caderinas/metabolismo , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Células HeLa , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Terapia de Alvo Molecular , Gradação de Tumores , Proteínas Proto-Oncogênicas c-met/biossíntese , Proteínas Proto-Oncogênicas c-met/genética , Receptores CXCR4/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
20.
Int J Oncol ; 44(6): 1853-60, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24728301

RESUMO

Cervical carcinoma is frequently diagnosed among women, particularly in low and middle income countries. In this study, we investigated the role of the SDF-1/CXCR4 axis during cervical carcinoma growth and progression in vitro and in vivo. Downregulation of CXCR4 receptor using an RNA interference system led to almost complete inhibition of the receptor expression, activation and function. CXCR4 receptor silencing led to decreased ability to signal, to induce migration and to form holoclone-like colonies, with no influence on viability/proliferation of the cells. CXCR4-deficient cells had also significantly lower levels of MMP-9. Interestingly, downregulation of CXCR4 expression resulted in reduced tumor growth in vivo. Tumors generated by CXCR4-deficient cells had also lower expression of the proliferation marker Ki­67 and decreased ability to engraft into lungs and spleen. Taken together, our results indicate that CXCR4 receptor may play an important role during cervical carcinoma invasion. In our study CXCR4 influenced invasive properties of cervical carcinoma cells both in vitro and in vivo.


Assuntos
Carcinoma/patologia , Invasividade Neoplásica/patologia , Receptores CXCR4/metabolismo , Neoplasias do Colo do Útero/patologia , Animais , Carcinoma/genética , Proliferação de Células/genética , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Pulmão/patologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos SCID , Invasividade Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias Experimentais , Receptores CXCR4/genética , Baço/patologia
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