Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.619
Filtrar
1.
Nat Commun ; 11(1): 4607, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929081

RESUMO

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Acrilamidas/farmacologia , Idoso de 80 Anos ou mais , Compostos de Anilina/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Imidazóis/farmacologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Pirazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
Am J Physiol Heart Circ Physiol ; 319(4): H730-H743, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795184

RESUMO

Insulin-like growth factor-1 (IGF-1) decreases atherosclerosis in apolipoprotein E (Apoe)-deficient mice when administered systemically. However, mechanisms for its atheroprotective effect are not fully understood. We generated endothelium-specific IGF-1 receptor (IGF1R)-deficient mice on an Apoe-deficient background to assess effects of IGF-1 on the endothelium in the context of hyperlipidemia-induced atherosclerosis. Endothelial deficiency of IGF1R promoted atherosclerotic burden, when animals were fed on a high-fat diet for 12 wk or normal chow for 12 mo. Under the normal chow feeding condition, the vascular relaxation response to acetylcholine was increased in the endothelial IGF1R-deficient aorta; however, feeding of a high-fat diet substantially attenuated the relaxation response, and there was no difference between endothelial IGF1R-deficient and control mice. The endothelium and its intercellular junctions provide a barrier function to the vasculature. In human aortic endothelial cells, IGF-1 upregulated occludin, claudin 5, VE-cadherin, JAM-A, and CD31 expression levels, and vice versa, specific IGF1R inhibitor, picropodophyllin, an IGF1R-neutralizing antibody (αIR3), or siRNA to IGF1R abolished the IGF-1 effects on junction and adherens proteins, suggesting that IGF-1 promoted endothelial barrier function. Moreover, endothelial transwell permeability assays indicated that inhibition of IGF-1 signaling elevated solute permeability through the monolayer of human aortic endothelial cells. In summary, endothelial IGF1R deficiency increases atherosclerosis, and IGF-1 positively regulates tight junction protein and adherens junction protein levels and endothelial barrier function. Our findings suggest that the elevation of the endothelial junction protein level is, at least in part, the mechanism for antiatherogenic effects of IGF-1.NEW & NOTEWORTHY Endothelial insulin-like growth factor-1 (IGF-1) receptor deficiency significantly elevated atherosclerotic burden in apolipoprotein E-deficient mice, mediated at least in part by downregulation of intercellular junction proteins and, thus, elevated endothelial permeability. This study revealed a novel role for IGF-1 in supporting endothelial barrier function. These findings suggest that IGF-1's ability to promote endothelial barrier function may offer a novel therapeutic strategy for vascular diseases such as atherosclerosis.


Assuntos
Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Permeabilidade Capilar , Células Endoteliais/metabolismo , Receptor IGF Tipo 1/deficiência , Animais , Antígenos CD/metabolismo , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/patologia , Caderinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais/patologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Placa Aterosclerótica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Células THP-1 , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/metabolismo
3.
J Anim Sci ; 98(9)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841331

RESUMO

Goose fatty liver may have a unique protective mechanism as it does not show a pathological injury even in the case of severe steatosis. Although neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4) participates in repair and regeneration of injured liver through its target proteins, its role in nonalcoholic fatty liver disease remains unknown. Using quantitative polymerase chain reaction (PCR) and immunoblot analyses, here, we found that the messenger RNA (mRNA) and protein expressions of NEDD4 were induced in goose fatty liver compared with normal liver. The mRNA expression of the gene of phosphate and tension homology deleted on chromosome ten (PTEN) and insulin-like growth factor 1 receptor (IGF1R) was also induced in goose fatty liver; however, their protein expression was or tended to be suppressed. Moreover, the co-immunoprecipitation analysis indicated that there was a physical association between NEDD4 and PTEN in goose liver, which was consistent with the ubiquitination of PTEN in goose fatty liver. Furthermore, NEDD4 overexpression in goose primary hepatocytes suppressed the PTEN and IGF1R protein levels without a significant effect on their mRNA expression. In conclusion, the increased expression of NEDD4 leads to the degradation of PTEN and IGF1R proteins through ubiquitination in goose fatty liver, suggesting that NEDD4 may protect goose fatty liver from severe steatosis-associated injury via its target proteins during the development of goose fatty liver.


Assuntos
Fígado Gorduroso/veterinária , Regulação da Expressão Gênica , Ubiquitina-Proteína Ligases Nedd4/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Doenças das Aves Domésticas/fisiopatologia , Receptor IGF Tipo 1/metabolismo , Animais , Fígado Gorduroso/fisiopatologia , Gansos , Masculino , Ubiquitina-Proteína Ligases Nedd4/genética , PTEN Fosfo-Hidrolase/genética , Proteólise , Receptor IGF Tipo 1/genética , Ubiquitina/metabolismo , Ubiquitinação
4.
PLoS One ; 15(7): e0236291, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701997

RESUMO

Nuclear IGF1R has been linked to poor outcome in cancer. We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequent IGF1R and PCNA colocalization in many cancer types. IGF1R/PCNA colocalization was more frequently increased in tumor cells than in adjacent normal, and more prominent in areas with dysplasia and invasion. However, the interaction was often lost in tumors with poor response to neoadjuvant treatment and most metastatic lesions. In two independent cohorts of serous ovarian carcinomas and oropharyngeal squamous cell carcinomas, stronger IGF1R/PCNA colocalization was significantly associated with a higher overall survival. Ex vivo irradiation of ovarian cancer tissue acutely induced IGF1R/PCNA colocalization together with γH2AX-foci formations. In vitro, RAD18 mediated mono-ubiquitination of PCNA during replication stress was dependent on IGF1R kinase activity. DNA fiber analysis revealed that IGF1R activation could rescue stalled DNA replication forks, but only in cancer cells with baseline IGF1R/PCNA interaction. We believe that the IGF1R/PCNA interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability. To exploit this mechanism in IGF1R targeted therapy, IGF1R inhibitors should be explored in the context of concomitant induction of DNA replication stress as well as in earlier clinical stages than previously tried.


Assuntos
Núcleo Celular/metabolismo , Dano ao DNA , Replicação do DNA , Neoplasias/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Receptor IGF Tipo 1/metabolismo , Linhagem Celular Tumoral , Humanos , Gradação de Tumores , Neoplasias/patologia , Neoplasias/terapia , Ligação Proteica , Análise de Sobrevida
5.
J Pharmacol Sci ; 144(2): 61-68, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32684333

RESUMO

The effects of adipokine administration to the hypothalamic preoptic area (POA), which is one of the body temperature (BT) regulation centers in the central nervous system, on BT were investigated in male Wistar rats. BT was measured in conscious rats using telemetry. Insulin-like growth factor-1 (IGF-1), interleukin-1ß (IL-1ß), monocyte chemoattractant protein-1 and lipocalin-2 produced hyperthermia, and the effects induced by IL-1ß (25 ng) and IGF-1 (5 µg) were sustainable and remarkable. IL-6 did not show any significant effect. The IGF-1-induced effect was inhibited by pretreatment with IGF binding protein 3 (IGFBP3) or NVP-AEW541 (NVP, a selective inhibitor of type 1 IGF receptor tyrosine kinase, IGF1R TK). NVP-induced inhibition was observed only in the early phase of IGF-1-induced hyperthermia. In addition, IGF-1 increased the IL-1ß concentration in the microdialysate of POA perfusion, but did not increase the IL-1ß concentration in the plasma or the PGE2 concentration in the microdialysate. These findings suggested that IGF-1 produced hyperthermia, which was mediated, at least a part, through an increased IL-1ß concentration after activation of IGF1R TK in the POA, and the IGF-IGFBP system possibly participates in BT homeostasis in the POA.


Assuntos
Adipocinas/administração & dosagem , Adipocinas/farmacologia , Temperatura Corporal/efeitos dos fármacos , Temperatura Corporal/genética , Área Pré-Óptica/metabolismo , Área Pré-Óptica/fisiologia , Animais , Quimiocina CCL2/administração & dosagem , Quimiocina CCL2/farmacologia , Febre/induzido quimicamente , Febre/genética , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/farmacologia , Interleucina-1beta/administração & dosagem , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Lipocalina-2/administração & dosagem , Lipocalina-2/farmacologia , Masculino , Proteínas Tirosina Quinases/metabolismo , Ratos Wistar , Receptor IGF Tipo 1/metabolismo
6.
Nature ; 583(7817): 615-619, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32494007

RESUMO

Pneumonia resulting from infection is one of the leading causes of death worldwide. Pulmonary infection by the respiratory syncytial virus (RSV) is a large burden on human health, for which there are few therapeutic options1. RSV targets ciliated epithelial cells in the airways, but how viruses such as RSV interact with receptors on these cells is not understood. Nucleolin is an entry coreceptor for RSV2 and also mediates the cellular entry of influenza, the parainfluenza virus, some enteroviruses and the bacterium that causes tularaemia3,4. Here we show a mechanism of RSV entry into cells in which outside-in signalling, involving binding of the prefusion RSV-F glycoprotein with the insulin-like growth factor-1 receptor, triggers the activation of protein kinase C zeta (PKCζ). This cellular signalling cascade recruits nucleolin from the nuclei of cells to the plasma membrane, where it also binds to RSV-F on virions. We find that inhibiting PKCζ activation prevents the trafficking of nucleolin to RSV particles on airway organoid cultures, and reduces viral replication and pathology in RSV-infected mice. These findings reveal a mechanism of virus entry in which receptor engagement and signal transduction bring the coreceptor to viral particles at the cell surface, and could form the basis of new therapeutics to treat RSV infection.


Assuntos
Receptor IGF Tipo 1/metabolismo , Receptores Virais/metabolismo , Vírus Sinciciais Respiratórios/metabolismo , Internalização do Vírus , Linhagem Celular , Núcleo Celular/metabolismo , Ativação Enzimática , Humanos , Fusão de Membrana/efeitos dos fármacos , Fosfoproteínas/metabolismo , Ligação Proteica , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Vírus Sinciciais Respiratórios/patogenicidade , Vírus Sinciciais Respiratórios/fisiologia , Carga Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
7.
Sci Rep ; 10(1): 8846, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483162

RESUMO

Rare or orphan diseases affect only small populations, thereby limiting the economic incentive for the drug development process, often resulting in a lack of progress towards treatment. Drug repositioning is a promising approach in these cases, due to its low cost. In this approach, one attempts to identify new purposes for existing drugs that have already been developed and approved for use. By applying the process of drug repositioning to identify novel treatments for rare diseases, we can overcome the lack of economic incentives and make concrete progress towards new therapies. Adrenocortical Carcinoma (ACC) is a rare disease with no practical and definitive therapeutic approach. We apply Heter-LP, a new method of drug repositioning, to suggest novel therapeutic avenues for ACC. Our analysis identifies innovative putative drug-disease, drug-target, and disease-target relationships for ACC, which include Cosyntropin (drug) and DHCR7, IGF1R, MC1R, MAP3K3, TOP2A (protein targets). When results are analyzed using all available information, a number of novel predicted associations related to ACC appear to be valid according to current knowledge. We expect the predicted relations will be useful for drug repositioning in ACC since the resulting ranked lists of drugs and protein targets can be used to expedite the necessary clinical processes.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Reposicionamento de Medicamentos/métodos , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Biologia Computacional , Cosintropina/uso terapêutico , DNA Topoisomerases Tipo II/metabolismo , Humanos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo
8.
Adv Cancer Res ; 147: 229-257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32593402

RESUMO

The insulin and insulin-like growth factor (IGF) family of proteins are part of a complex network that regulates cell proliferation and survival. While this system is undoubtedly important in prenatal development and postnatal cell growth, members of this family have been implicated in several different cancer types. Increased circulating insulin and IGF ligands have been linked to increased risk of cancer incidence. This observation has led to targeting the IGF system as a therapeutic strategy in a number of cancers. This chapter aims to describe the well-characterized biology of the IGF1R system, outline the rationale for targeting this system in cancer, summarize the clinical data as it stands, and discuss where we can go from here.


Assuntos
Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Terapia de Alvo Molecular , Neoplasias/patologia , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais
9.
Zhonghua Zhong Liu Za Zhi ; 42(5): 391-395, 2020 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-32482028

RESUMO

Objective: To investigate the expression of IGF1R-Ras and RAGE-HMGB1 signaling pathways in colorectal cancer patients with type 2 diabetes mellitus and their significance. Methods: The resected cancer tissues were obtained from 59 patients with colorectal cancer (CRC), including 29 patients with type 2 diabetes mellitus (CRC/DM group) and 30 with CRC alone (CRC group). The expressions of IGF1R, Ras, RAGE and HMGB1 in cancer tissues were detected by immunohistochemistry. The differences between the two groups were compared and the relationship between the expression and clinicopathological characteristics was analyzed. Results: In CRC/DM group, the positive rates of IGF1R and Ras were both 65.5% (19/29), and 51.7% (15/29) patients had IGF1R+ Ras+ immunophenotype, which were significantly higher than those in CRC group [33.3% (10/30), 36.7% (11/30) and 20.0% (6/30); P=0.013, 0.027 and 0.011, respectively]. The expression of IGF1R and Ras in CRC / DM group was positively correlated (r=0.479, P=0.017). The positive rate of RAGE expression in CRC group and CRC/DM group was 70.0% (21/30) and 72.4% (21/29) respectively, and the positive rate of HMGB1 expression was 46.7% (14/30) and 58.6% (17/29) respectively, neither was observed with significant difference (P=0.358 and 0.838). However, the proportion of patients with RAGE+ HMGB1+ immunophenotype in CRC/DM group [55.2% (16/29)] was higher than that in CRC Group [26.7% (8/30)] which was statistically significant (P=0.026), and the expression of both proteins was positively correlated in CRC/DM group (r=0.578, P=0.003). The clinicopathological analysis showed that in both groups the expression of IGF1R, Ras, RAGE and HMGB1 had no correlation with the sex, age, differentiation degree, tumor length, T stage and lymph node metastasis (P>0.05). Conclusion: Both IGF1R-Ras and RAGE-HMGB1 pathways may be involved in the oncogenesis of colorectal cancer in patients with type 2 diabetes.


Assuntos
Neoplasias Colorretais/patologia , Diabetes Mellitus Tipo 2/complicações , Genes ras/genética , Proteína HMGB1/metabolismo , Receptor IGF Tipo 1/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/complicações , Neoplasias Colorretais/metabolismo , Proteína HMGB1/genética , Humanos , Prognóstico , Receptor IGF Tipo 1/genética
10.
Breast Cancer Res ; 22(1): 40, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32393319

RESUMO

BACKGROUND: Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women. METHODS: We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) > 4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC). RESULTS: Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women than in White women (1.9 ± 1.2 vs 1.3 ± 1.4, p = 0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p = 0.004). HOMA-IR was positively associated with NPI score (r = 0.1, p = 0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (ß = 0.04, 95% CI 0.005-0.009, p = 0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p = 0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R >  1: 4.2 ± 0.8 vs IR/IGF-1R = 1: 3.9 ± 0.8 vs IR/IGF-1R < 1: 3.5 ± 1.0, p < 0.0001). CONCLUSIONS: In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.


Assuntos
Afro-Americanos/estatística & dados numéricos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Resistência à Insulina , Neoplasias da Mama/metabolismo , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Estados Unidos/epidemiologia
11.
Ann Otol Rhinol Laryngol ; 129(10): 1011-1019, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32468823

RESUMO

OBJECTIVES: Tunisia is in the endemic area of nasopharyngeal carcinoma. Epstein-Barr virus (EBV) based assays have been commonly used as standard markers for screening and monitoring the disease. So, it is very important to find novel factors for the early diagnostic and prognostic evaluation of this cancer. The aim of the study was to evaluate the expression of IGF-1R (Insulin Growth Factor Receptor 1), LMP 1 (Latent Membrane Protein 1) and EBERs (EBV encoded RNAs) in order to determine their correlation with clinicopathologic parameters and survival rates in patients with nasopharyngeal carcinoma (NPC). We also looked for the relationship between these biomarkers. METHODS: IGF-1R and LMP1 expression was performed by means of immunohistochemical method and EBERs were detected using in situ hybridization of paraffin embedded tumor tissues of 94 patients with nasopharyngeal carcinoma and 45 non-cancerous nasopharyngeal mucosa samples. RESULTS: Our findings demonstrated that IGF-1R was over expressed in 47.87% of NPC patients and only in 2.22% of controls. Positive LMP1 expression was detected in 56.38% of NPC patients and all NPC patients were positive for the EBV-encoded RNAs staining. A statistically significant positive correlation was observed between IGF-1R expression and the tumor size (P < .001). Kaplan-Meier survival curves showed that NPC patients with a strong IGF-1R expression level have shorter median and 5-year Overall Survival than those with weak expression rates (100.15 vs 102.68 months, P = .08). In addition, median and 5-year Disease-Free Survival was significantly lower in the LMP1 positive NPC patients than in the LMP1 negative ones (53.38 vs 93.37 months, P = .03). Moreover, LMP1 expression correlated strongly with IGF-1R expression (P = .018). The relationship between these two biomarkers could influence patient survival. CONCLUSION: IGF1-R and LMP1 could be valuable prognostic markers in Tunisian NPC patients.


Assuntos
Infecções por Vírus Epstein-Barr/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , RNA Viral/metabolismo , Receptor IGF Tipo 1/metabolismo , Proteínas da Matriz Viral/metabolismo , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Nasofaringe/metabolismo , Prognóstico , Mucosa Respiratória/metabolismo , Taxa de Sobrevida , Tunísia , Adulto Jovem
12.
Int J Nanomedicine ; 15: 2647-2658, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368046

RESUMO

Purpose: Myocardial ischemia-reperfusion injury primarily causes myocardial infarction (MI), which is manifested by cell death. Angiogenesis is essential for repair and regeneration in cardiac tissue after MI. In this study, we aimed to investigate the effect of exosomes derived from the serum of MI patients in angiogenesis and its related mechanism. Patients and Methods: Exosomes, isolated from serum, were collected from MI (MI-exosome) and control (Con-exosome) patients. After coculturing with human umbilical vein endothelial cells, MI-exosome promoted cell proliferation, migration, and tube formation. Results: The results revealed that the production and release of MI-exosome were associated with cardiomyocytes. Moreover, microarray assays demonstrated that miRNA-143 was significantly decreased in MI-exosome. Meanwhile, the overexpression and knockdown of miRNA-143 could inhibit and enhance angiogenesis, respectively. Furthermore, the effect of exosomal miRNA-143 on angiogenesis was mediated by its targeting gene, insulin-like growth factor 1 receptor (IGF-IR), and was associated with the production of nitric oxide (NO). Conclusion: Taken together, exosomes derived from the serum of patients with MI promoted angiogenesis through the IGF-IR/NO signaling pathway. The results provide novel understanding of the function of exosomes in MI.


Assuntos
Vasos Coronários/metabolismo , Exossomos/metabolismo , MicroRNAs/metabolismo , Infarto do Miocárdio/sangue , Neovascularização Fisiológica , Receptor IGF Tipo 1/metabolismo , Animais , Linhagem Celular , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Óxido Nítrico/biossíntese , Transdução de Sinais
13.
Nature ; 580(7801): 136-141, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32238925

RESUMO

Cancer genomics studies have identified thousands of putative cancer driver genes1. Development of high-throughput and accurate models to define the functions of these genes is a major challenge. Here we devised a scalable cancer-spheroid model and performed genome-wide CRISPR screens in 2D monolayers and 3D lung-cancer spheroids. CRISPR phenotypes in 3D more accurately recapitulated those of in vivo tumours, and genes with differential sensitivities between 2D and 3D conditions were highly enriched for genes that are mutated in lung cancers. These analyses also revealed drivers that are essential for cancer growth in 3D and in vivo, but not in 2D. Notably, we found that carboxypeptidase D is responsible for removal of a C-terminal RKRR motif2 from the α-chain of the insulin-like growth factor 1 receptor that is critical for receptor activity. Carboxypeptidase D expression correlates with patient outcomes in patients with lung cancer, and loss of carboxypeptidase D reduced tumour growth. Our results reveal key differences between 2D and 3D cancer models, and establish a generalizable strategy for performing CRISPR screens in spheroids to reveal cancer vulnerabilities.


Assuntos
Sistemas CRISPR-Cas/genética , Técnicas de Cultura de Células/métodos , Proliferação de Células/genética , Genoma Humano/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Esferoides Celulares/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Motivos de Aminoácidos , Animais , Carboxipeptidases/antagonistas & inibidores , Carboxipeptidases/deficiência , Carboxipeptidases/genética , Carboxipeptidases/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Terapia de Alvo Molecular , Mutação , Fenótipo , Receptor IGF Tipo 1/química , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Esferoides Celulares/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Cancer Invest ; 38(5): 289-299, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32308049

RESUMO

The aim was to evaluate the clinical impact of IGF-1/IGF-1R in Tunisian laryngeal carcinoma. A high IGF-1R immunohistochemical expression was found in our series (81.43%). A tendency toward an association between IGF-1R expression and lymph node metastasis was found (p = 0.068). Patients with positive IGF-1R expression showed a short disease free survival (p = 0.053) and a high recurrence rate. Furthermore, circulating IGF-1 levels sera, detected by ELISA, were higher among patients compared to controls (p < 0.001). IGF-1R might have a prognostic significance and could be a factor of tumor recurrence. However, high levels of IGF-1 increase the risk of developing of LSCC disease.


Assuntos
Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Receptor IGF Tipo 1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica/métodos , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Tunísia
15.
Endocrinology ; 161(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32147716

RESUMO

Glucagon-like peptide-2 (GLP-2) is an intestinotrophic hormone that promotes intestinal growth and proliferation through downstream mediators, including epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1). EGF synergistically enhances the proliferative actions of IGF-1 in intestinal cell lines, and both of these factors are known to be essential for the trophic effects of GLP-2 in vivo. However, whether EGF and IGF-1 interact to mediate the proliferative actions of GLP-2 in vivo remains unknown. Normal and knockout (KO) mice lacking the intestinal epithelial IGF-1 receptor (IE-IGF-1R) were therefore treated chronically with EGF and/or long-acting human hGly2GLP-2, followed by determination of intestinal growth parameters. Intestines from control and IE-IGF-1R KO mice were also used to generate organoids (which lack the GLP-2 receptor) and were treated with EGF and/or IGF-1. Combination treatment with EGF and hGly2GLP-2 increased small intestinal weight and crypt-villus height in C57Bl/6 mice in an additive manner, whereas only hGly2GLP-2 treatment increased crypt cell proliferation. However, although combination treatment also increased small intestinal weight and crypt-villus height in IE-IGF-1R KO mice, the proliferative responses to hGly2GLP-2 alone or with EGF were diminished in these animals. Finally, IGF-1 treatment of organoids undergoing EGF withdrawal was not additive to the effect of EGF replacement on proliferation, but could restore normal proliferation in the absence of EGF. Together, these findings demonstrate that the intestinal proliferative effects of hGly2GLP-2 are augmented by exogenous EGF in a manner that is partially dependent upon IE-IGF-1R signaling.


Assuntos
Fator de Crescimento Epidérmico/farmacologia , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Intestino Delgado/metabolismo , Camundongos , Camundongos Knockout , Receptor IGF Tipo 1/genética , Transdução de Sinais/efeitos dos fármacos
16.
Biomed Res Int ; 2020: 4150735, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190664

RESUMO

Objective: The aim of this study was to investigate the expression of Snail, galectin-3, and IGF1R in benign and malignant pheochromocytoma and paraganglioma (PPGL) and explore their role in the diagnosis of malignant PPGL. Methods: We retrospectively collected and analyzed surgical tumor tissue from 226 patients initially diagnosed with PPGL who underwent surgery from Jan. 2009 to Jan. 2016 at West China Hospital, Sichuan University. We observed and quantified the expression of Snail, galectin-3, and IGF1R in paraffin-embedded samples by immunohistochemical staining. Results: The significant difference in survival time among the three groups (benign PHEO, benign PGL, and potentially malignant PPGL) was compared by Kaplan-Meier survival analysis. The positive staining of Snail, galectin-3, and IGF1R in the benign PHEO group was significantly lower than that in the other three groups (P < 0.001). The Kaplan-Meier survival plots indicated that the survival time of the patients with intense positive staining was significantly lower than that of the patients with weak positive staining. Conclusion: The intense expression of Snail, galectin-3, and IGF1R may be valuable indicators for the diagnosis of malignant PPGL.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Biomarcadores Tumorais/metabolismo , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Receptor IGF Tipo 1/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/cirurgia , Adulto , Idoso , China , Diagnóstico Diferencial , Feminino , Galectina 3/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Paraganglioma/metabolismo , Paraganglioma/cirurgia , Feocromocitoma/metabolismo , Feocromocitoma/cirurgia , Estudos Retrospectivos , Software
17.
Oncogene ; 39(14): 2921-2933, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32029900

RESUMO

High-grade serous carcinoma, accounts for up to 70% of all ovarian cases. Furin, a proprotein convertase, is highly expressed in high-grade serous carcinoma of ovarian cancer patients, and its expression is even higher in tumor omentum than in normal omentum, the preferred site of ovarian cancer metastasis. The proteolytic actions of this cellular endoprotease help the maturation of several important precursors of protein substrates and its levels increase the risk of several cancer. We show that furin activates the IGF1R/STAT3 signaling axis in ovarian cancer cells. Conversely, furin knockdown downregulated IGF1R-ß and p-STAT3 (Tyr705) expression. Further, silencing furin reduced tumor cell migration and invasion in vitro and tumor growth and metastasis in vivo. Collectively, our findings show that furin can be an effective therapeutic target for ovarian cancer prevention or treatment.


Assuntos
Furina/metabolismo , Invasividade Neoplásica/patologia , Neoplasias Ovarianas/metabolismo , Receptor ErbB-3/metabolismo , Receptor IGF Tipo 1/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Progressão da Doença , Regulação para Baixo/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Ovarianas/patologia
18.
Oncogene ; 39(17): 3604-3610, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32060422

RESUMO

The beneficial effects of lipoic acid (LA) in cancer treatment have been well documented in the last decade. Indeed, LA exerts crucial antiproliferative effects by reducing breast cancer cell viability, cell cycle progression and the epithelial-to-mesenchymal transition (EMT). However, the mechanisms of action (MOA) underlying these antiproliferative effects remain to be elucidated. Recently, we demonstrated that LA decreases breast cancer cell proliferation by inhibiting IGF-1R maturation via the downregulation of the proprotein convertase furin. The aim of the present study was to investigate the MOA by which LA inhibits furin expression in estrogen receptor α (ERα) (+) and (-) breast cancer cell lines. We unveil that LA exerts a pro-oxidant effect on these cell lines, the resulting reactive oxygen species (ROS) generated being responsible for the reduction in the expression of the major (CREB) protein. This transcription factor is overexpressed in many types of cancers and regulates the expression of furin in breast cancer cells independently of ERα, as evidenced herein by the inhibition of furin expression following CREB silencing. Consequently, our findings expose for the first time the complete MOA of LA via the CREB/furin axis leading to inhibition of breast cancer cell proliferation.


Assuntos
Neoplasias da Mama/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Furina/metabolismo , Proteínas de Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Ácido Tióctico/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7
19.
Int J Mol Sci ; 21(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046161

RESUMO

Dexamethasone (Dex) has been widely used as a potent anti-inflammatory, antishock, and immunosuppressive agent. However, high dose or long-term use of Dex is accompanied by side effects including skeletal muscle atrophy, whose underlying mechanisms remain incompletely understood. A number of microRNAs (miRNAs) have been shown to play key roles in skeletal muscle atrophy. Previous studies showed significantly increased miR-322 expression in Dex-treated C2C12 myotubes. In our study, the glucocorticoid receptor (GR) was required for Dex to increase miR-322 expression in C2C12 myotubes. miR-322 mimic or miR-322 inhibitor was used for regulating the expression of miR-322. Insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (INSR) were identified as target genes of miR-322 using luciferase reporter assays and played key roles in Dex-induced muscle atrophy. miR-322 overexpression promoted atrophy in Dex-treated C2C12 myotubes and the gastrocnemius muscles of mice. Conversely, miR-322 inhibition showed the opposite effects. These data suggested that miR-322 contributes to Dex-induced muscle atrophy via targeting of IGF1R and INSR. Furthermore, miR-322 might be a potential target to counter Dex-induced muscle atrophy. miR-322 inhibition might also represent a therapeutic approach for Dex-induced muscle atrophy.


Assuntos
MicroRNAs/genética , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/metabolismo , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Animais , Linhagem Celular , Dexametasona/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/etiologia , Atrofia Muscular/genética , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo
20.
Immunity ; 52(2): 275-294.e9, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32075728

RESUMO

Type 3 innate lymphoid cells (ILC3s) are critical for lung defense against bacterial pneumonia in the neonatal period, but the signals that guide pulmonary ILC3 development remain unclear. Here, we demonstrated that pulmonary ILC3s descended from ILC precursors that populated a niche defined by fibroblasts in the developing lung. Alveolar fibroblasts produced insulin-like growth factor 1 (IGF1), which instructed expansion and maturation of pulmonary ILC precursors. Conditional ablation of IGF1 in alveolar fibroblasts or deletion of the IGF-1 receptor from ILC precursors interrupted ILC3 biogenesis and rendered newborn mice susceptible to pneumonia. Premature infants with bronchopulmonary dysplasia, characterized by interrupted postnatal alveolar development and increased morbidity to respiratory infections, had reduced IGF1 concentrations and pulmonary ILC3 numbers. These findings indicate that the newborn period is a critical window in pulmonary immunity development, and disrupted lung development in prematurely born infants may have enduring effects on host resistance to respiratory infections.


Assuntos
Imunidade Inata , Fator de Crescimento Insulin-Like I/metabolismo , Pulmão/imunologia , Linfócitos/citologia , Células Epiteliais Alveolares/metabolismo , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/imunologia , Diferenciação Celular , Proliferação de Células , Suscetibilidade a Doenças/imunologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Fator de Crescimento Insulin-Like I/deficiência , Interleucinas/metabolismo , Pulmão/citologia , Pulmão/crescimento & desenvolvimento , Linfócitos/metabolismo , Camundongos , Pneumonia/imunologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA