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1.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445345

RESUMO

Chondrosarcoma is a malignant bone tumor that is characterized by high metastatic potential and marked resistance to radiation and chemotherapy. The knowledge that adipokines facilitate the initiation, progression, metastasis, and treatment resistance of various tumors has driven several in vitro and in vivo investigations into the effects of adipokines resistin, leptin, and adiponectin upon the development and progression of chondrosarcomas. Another adipokine, visfatin, is known to regulate tumor progression and metastasis, although how this molecule may affect chondrosarcoma metastasis is unclear. Here, we found that visfatin facilitated cellular migration via matrix metalloproteinase-2 (MMP-2) production in human chondrosarcoma cells and overexpression of visfatin enhanced lung metastasis in a mouse model of chondrosarcoma. Visfatin-induced stimulation of MMP-2 synthesis and activation of the AP-1 transcription factor facilitated chondrosarcoma cell migration via the ERK, p38, and JNK signaling pathways. This evidence suggests that visfatin is worth targeting in the treatment of metastatic chondrosarcoma.


Assuntos
Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Citocinas/fisiologia , Metaloproteinase 2 da Matriz/genética , Nicotinamida Fosforribosiltransferase/fisiologia , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Condrossarcoma/genética , Condrossarcoma/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição AP-1/fisiologia , Células Tumorais Cultivadas
2.
Eur J Pharmacol ; 908: 174374, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34303662

RESUMO

The efficacy of corticosteroids and its use for the treatment of SARS-CoV-2 infections is controversial. In this study, using data sets of SARS-CoV-2 infected lung tissues and nasopharyngeal swabs, as well as in vitro experiments, we show that SARS-CoV-2 infection significantly downregulates DUSP1 expression. This downregulation of DUSP1 could be the mechanism regulating the enhanced activation of MAPK pathway as well as the reported steroid resistance in SARS-CoV-2 infection. Moreover, chloroquine, an off labeled COVID-19 drug is able to induce DUSP1 and attenuate MAPK pathway; and is expected to improve sensitivity to steroid treatment. However, further mechanistic studies are required to confirm this effect.


Assuntos
COVID-19/tratamento farmacológico , Cloroquina/farmacologia , Fosfatase 1 de Especificidade Dupla/genética , Glucocorticoides/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Idoso , COVID-19/patologia , COVID-19/virologia , Estudos de Casos e Controles , Células Cultivadas , Cloroquina/uso terapêutico , Conjuntos de Dados como Assunto , Regulação para Baixo/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Sinergismo Farmacológico , Fosfatase 1 de Especificidade Dupla/metabolismo , Fibroblastos , Glucocorticoides/uso terapêutico , Voluntários Saudáveis , Humanos , Pulmão/citologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Pessoa de Meia-Idade , Nasofaringe/virologia , Uso Off-Label , Cultura Primária de Células , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/patogenicidade
3.
Anticancer Res ; 41(7): 3349-3361, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230131

RESUMO

BACKGROUND/AIM: The present study investigated the oncogenic functions of TACC3 in the progression of gastric cancer (GC). MATERIALS AND METHODS: We analysed TACC3 in relation to cell growth, invasion capability, expression of epithelial-mesenchymal transition (EMT)-related markers, and ERK/Akt/cyclin D1 signaling factors. The correlation between the immunohistochemically confirmed expression of TACC3 and clinical factors was also analyzed. RESULTS: The increased proliferation and invasion of TACC3-over-expressing GC cells was accompanied by altered regulation of EMT-associated markers and activation of ERK/Akt/cyclin D1 signaling. Immunohistochemical analysis of TACC3 in human GC tissues revealed that its expression is correlated with aggressive characteristics and poor prognosis of intestinal-type GC. CONCLUSION: TACC3 contributes to gastric tumorigenesis by promoting EMT via the ERK/Akt/cyclin D1 signaling pathway. The correlation between TACC3 expression and multiple clinicopathological variables implies that its effective therapeutic targeting in GC will depend on the tumor subtype.


Assuntos
Carcinogênese/genética , Ciclina D1/genética , Transição Epitelial-Mesenquimal/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Gástricas/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Transdução de Sinais/genética , Estômago/patologia , Neoplasias Gástricas/patologia
4.
Gene ; 800: 145836, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34280510

RESUMO

Skeletal muscle atrophy can result from a range of physiological conditions, including denervation, immobilization, hindlimb unweighting, and aging. To better characterize the molecular genetic events of atrophy, a microarray analysis revealed that FGGY carbohydrate kinase domain containing (Fggy) is expressed in skeletal muscle and is induced in response to denervation. Bioinformatic analysis of the Fggy gene locus revealed two validated isoforms with alternative transcription initiation sites that we have designated Fggy-L-552 and Fggy-S-387. Additionally, we cloned two novel alternative splice variants, designated Fggy-L-482 and Fggy-S-344, from cultured muscle cells suggesting that at least four Fggy splice variants are expressed in skeletal muscle. Quantitative RT-PCR was performed using RNA isolated from muscle cells and primers designed to distinguish the four alternative Fggy transcripts and found that the Fggy-L transcripts are more highly expressed during myoblast differentiation, while the Fggy-S transcripts show relatively stable expression in proliferating myoblasts and differentiated myotubes. Confocal fluorescent microscopy revealed that the Fggy-L variants appear to localize evenly throughout the cytoplasm, while the Fggy-S variants produce a more punctuate cytoplasmic localization pattern in proliferating muscle cells. Finally, ectopic expression of Fggy-L-552 and Fggy-S-387 resulted in inhibition of muscle cell differentiation and attenuation of the MAP kinase and Akt signaling pathways. The identification and characterization of novel genes such as Fggy helps to improve our understanding of the molecular and cellular events that lead to atrophy and may eventually result in the identification of new therapeutic targets for the treatment of muscle wasting.


Assuntos
Músculo Esquelético/enzimologia , Atrofia Muscular/genética , Fosfotransferases/genética , Fosfotransferases/metabolismo , Sítios de Splice de RNA , Animais , Diferenciação Celular/genética , Células Cultivadas , Citoplasma/enzimologia , Regulação Enzimológica da Expressão Gênica , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Mioblastos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
5.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204949

RESUMO

Idiopathic pulmonary fibrosis (IPF) is one of the most symptomatic progressive fibrotic lung diseases, in which patients have an extremely poor prognosis. Therefore, understanding the precise molecular mechanisms underlying pulmonary fibrosis is necessary for the development of new therapeutic options. Stress-activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) are ubiquitously expressed in various types of cells and activated in response to cellular environmental stresses, including inflammatory and apoptotic stimuli. Type II alveolar epithelial cells, fibroblasts, and macrophages are known to participate in the progression of pulmonary fibrosis. SAPKs can control fibrogenesis by regulating the cellular processes and molecular functions in various types of lung cells (including cells of the epithelium, interstitial connective tissue, blood vessels, and hematopoietic and lymphoid tissue), all aspects of which remain to be elucidated. We recently reported that the stepwise elevation of intrinsic p38 signaling in the lungs is correlated with a worsening severity of bleomycin-induced fibrosis, indicating an importance of this pathway in the progression of pulmonary fibrosis. In addition, a transcriptome analysis of RNA-sequencing data from this unique model demonstrated that several lines of mechanisms are involved in the pathogenesis of pulmonary fibrosis, which provides a basis for further studies. Here, we review the accumulating evidence for the spatial and temporal roles of SAPKs in pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , MAP Quinase Quinase 4/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Vasos Sanguíneos/enzimologia , Vasos Sanguíneos/crescimento & desenvolvimento , Fibroblastos/enzimologia , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/patologia , Pulmão/embriologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/genética , Macrófagos/enzimologia
6.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201614

RESUMO

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.


Assuntos
Cromossomos Humanos Par 3/genética , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/genética , Monossomia , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Uveais/genética , Linhagem Celular Tumoral , Variações do Número de Cópias de DNA , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Iniciação 2 em Eucariotos/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Sulfonamidas/farmacologia , Análise de Sobrevida , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/mortalidade
7.
Development ; 148(13)2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34104941

RESUMO

Zygotic genomic activation (ZGA) is a landmark event in the maternal-to-zygotic transition (MZT), and the regulation of ZGA by maternal factors remains to be elucidated. In this study, the depletion of maternal ring finger protein 114 (RNF114), a ubiquitin E3 ligase, led to developmental arrest of two-cell mouse embryos. Using immunofluorescence and transcriptome analysis, RNF114 was proven to play a crucial role in major ZGA. To study the underlying mechanism, we performed protein profiling in mature oocytes and found a potential substrate for RNF114, chromobox 5 (CBX5), ubiquitylation and degradation of which was regulated by RNF114. The overexpression of CBX5 prevented embryonic development and impeded major ZGA. Furthermore, TAB1 was abnormally accumulated in mutant two-cell embryos, which was consistent with the result of in vitro knockdown of Rnf114. Knockdown of Cbx5 or Tab1 in maternal RNF114-depleted embryos partially rescued developmental arrest and the defect of major ZGA. In summary, our study reveals that maternal RNF114 plays a precise role in degrading some important substrates during the MZT, the misregulation of which may impede the appropriate activation of major ZGA in mouse embryos.


Assuntos
Desenvolvimento Embrionário/fisiologia , Genoma , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Zigoto/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas Cromossômicas não Histona/genética , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Fatores de Transcrição/metabolismo , Transcriptoma
8.
Nat Commun ; 12(1): 3392, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099666

RESUMO

Cells infected with pathogens can contribute to clearing infections by releasing signals that instruct neighbouring cells to mount a pro-inflammatory cytokine response, or by other mechanisms that reduce bystander cells' susceptibility to infection. Here, we show the opposite effect: epithelial cells infected with Salmonella Typhimurium secrete host factors that facilitate the infection of bystander cells. We find that the endoplasmic reticulum stress response is activated in both infected and bystander cells, and this leads to activation of JNK pathway, downregulation of transcription factor E2F1, and consequent reprogramming of microRNA expression in a time-dependent manner. These changes are not elicited by infection with other bacterial pathogens, such as Shigella flexneri or Listeria monocytogenes. Remarkably, the protein HMGB1 present in the secretome of Salmonella-infected cells is responsible for the activation of the IRE1 branch of the endoplasmic reticulum stress response in non-infected, neighbouring cells. Furthermore, E2F1 downregulation and the associated microRNA alterations promote Salmonella replication within infected cells and prime bystander cells for more efficient infection.


Assuntos
Efeito Espectador/genética , Fator de Transcrição E2F1/metabolismo , MicroRNAs/metabolismo , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Animais , Efeito Espectador/imunologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Fator de Transcrição E2F1/genética , Estresse do Retículo Endoplasmático/imunologia , Endorribonucleases/metabolismo , Proteína HMGB1/metabolismo , Células HeLa , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Listeria monocytogenes/imunologia , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , RNA-Seq , Infecções por Salmonella/genética , Infecções por Salmonella/microbiologia , Salmonella typhimurium/patogenicidade , Shigella flexneri/imunologia , Suínos
9.
Hematol Oncol ; 39 Suppl 1: 15-23, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105821

RESUMO

Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.


Assuntos
Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Dendríticas , Histiocitose de Células de Langerhans , Medicina de Precisão , Linfócitos T , Substituição de Aminoácidos , Diferenciação Celular/genética , Movimento Celular/genética , Células Dendríticas/imunologia , Células Dendríticas/patologia , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
10.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070465

RESUMO

Environmental or abiotic stresses are a common threat that remains a constant and common challenge to all plants. These threats whether singular or in combination can have devastating effects on plants. As a semiaquatic plant, rice succumbs to the same threats. Here we systematically look into the involvement of salicylic acid (SA) in the regulation of abiotic stress in rice. Studies have shown that the level of endogenous salicylic acid (SA) is high in rice compared to any other plant species. The reason behind this elevated level and the contribution of this molecule towards abiotic stress management and other underlying mechanisms remains poorly understood in rice. In this review we will address various abiotic stresses that affect the biochemistry and physiology of rice and the role played by SA in its regulation. Further, this review will elucidate the potential mechanisms that control SA-mediated stress tolerance in rice, leading to future prospects and direction for investigation.


Assuntos
Regulação da Expressão Gênica de Plantas/fisiologia , Oryza/metabolismo , Ácido Salicílico/metabolismo , Estresse Fisiológico/fisiologia , Resposta ao Choque Frio/fisiologia , Secas , Regulação da Expressão Gênica de Plantas/genética , Resposta ao Choque Térmico/fisiologia , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Metais/metabolismo , Metais/toxicidade , Oryza/enzimologia , Reguladores de Crescimento de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Salino/fisiologia
11.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072833

RESUMO

We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and intratracheally administered nitrogen mustard (NM)) and investigated male-female differences. Female mice exhibited higher 30-day survival and less weight loss than male mice. Thirty days after the instillation of either HCl or NM, bronchoalveolar lavage fluid displayed a persistent, mild inflammatory response, but with higher white blood cell numbers and total protein content in males vs. females. Furthermore, females exhibited less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores. After instillation of either HCl or NM, all animals displayed increased values of phosphorylated (activated) Heat Shock Protein 90, which plays a crucial role in the alveolar wound-healing processes; however, females presented lower activation of both transforming growth factor-ß (TGF-ß) signaling pathways: ERK and SMAD. We propose that female mice are protected from chronic complications of a single exposure to either HCl or NM through a lesser activation of TGF-ß and downstream signaling. The understanding of the molecular mechanisms that confer a protective effect in females could help develop new, gender-specific therapeutics for IPF.


Assuntos
Colágeno/genética , Proteínas de Choque Térmico HSP90/genética , Fibrose Pulmonar Idiopática/genética , Fator de Crescimento Transformador beta/genética , Animais , Feminino , Regulação da Expressão Gênica/genética , Humanos , Ácido Clorídrico/toxicidade , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mecloretamina/toxicidade , Camundongos , Proteínas Smad/genética
12.
Nat Commun ; 12(1): 2606, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972557

RESUMO

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Células Th17/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/imunologia , Sinergismo Farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células Th17/imunologia , Proteína Supressora de Tumor p53/metabolismo
13.
Mol Cell Biochem ; 476(10): 3655-3670, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34052945

RESUMO

As a response to pro-inflammatory signals mesenchymal stem cells (MSCs) secrete agents and factors leading to lymphocyte recruitment, counteracting inflammation, and stimulating immunosuppression. On a molecular level, the signalling mediator TGF-ß-activated kinase 1 (TAK1) is activated by many pro-inflammatory signals, plays a critical role in inflammation and regulates innate and adaptive immune responses as well. While the role of TAK1 as a signalling factor promoting inflammation is well documented, we also considered a role for TAK1 in anti-inflammatory actions exerted by activated MSCs. We, therefore, investigated the capacity of lipopolysaccharide (LPS)-treated murine MSCs with lentivirally modulated TAK1 expression levels to recruit lymphocytes. TAK1 downregulated by lentiviral vectors expressing TAK1 shRNA in murine MSCs interfered with the capacity of murine MSCs to chemoattract lymphocytes, indeed. Analysing a pool of 84 secreted factors we found that among 26 secreted cytokines/factors TAK1 regulated expression of one cytokine in LPS-activated murine MSCs in particular: interleukin-6 (IL-6). IL-6 in LPS-treated MSCs was responsible for lymphocyte recruitment as substantiated by neutralizing antibodies. Our studies, therefore, suggest that in LPS-treated murine MSCs the inflammatory signalling mediator TAK1 may exert anti-inflammatory properties via IL-6.


Assuntos
Interleucina-6/imunologia , Lipopolissacarídeos/farmacologia , Linfócitos/imunologia , MAP Quinase Quinase Quinases/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Animais , Células HEK293 , Humanos , Interleucina-6/genética , MAP Quinase Quinase Quinases/genética , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos
14.
Aging (Albany NY) ; 13(10): 14198-14218, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34016787

RESUMO

We investigated the role of long non-coding RNA (lncRNA) LOC146880 in esophageal squamous cell carcinoma (ESCC). LOC146880 was significantly upregulated in ESCC tissues (n = 21) and cell lines compared to the corresponding controls. Higher LOC146880 expression correlated with poorer overall survival (OS) of ESCC patients. Moreover, CREB-binding protein (CBP) and H3K27 acetylation levels were significantly higher in the LOC146880 promoter in ESCC cell lines than in the controls. LOC146880 silencing inhibited in vitro proliferation, invasion, migration, and epithelial-mesenchymal transition of ESCC cells. LOC146880 silencing also induced G1-phase cell cycle arrest and apoptosis in ESCC cells. Bioinformatics analysis, dual luciferase reporter assays, and RNA immunoprecipitation assays showed that LOC146880 regulates FSCN1 expression in ESCC cells by sponging miR-328-5p. Moreover, FSCN1 expression correlated with activation of the MAPK signaling pathway in ESCC cells and tissues. In vivo xenograft tumor volume and liver metastasis were significantly reduced in nude mice injected with LOC146880-silenced ESCC cells as compared to those injected with control shRNA-transfected ESCC cells. These findings show that the LOC146880/miR-328-5p/FSCN1/MAPK axis regulates ESCC progression in vitro and in vivo. LOC146880 is thus a promising prognostic biomarker and potential therapeutic target in ESCC.


Assuntos
Proteínas de Transporte/metabolismo , Progressão da Doença , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Sistema de Sinalização das MAP Quinases/genética , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , RNA Longo não Codificante/metabolismo , Acetilação , Sequência de Bases , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Histonas/metabolismo , Humanos , Lisina/metabolismo , Proteínas dos Microfilamentos/genética , Fragmentos de Peptídeos/metabolismo , RNA Longo não Codificante/genética , Sialoglicoproteínas/metabolismo , Transcrição Genética
15.
Aging (Albany NY) ; 13(9): 12780-12799, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33973871

RESUMO

In this study, we investigated the role of circular RNA_30032 (circRNA_30032) in renal fibrosis and the underlying mechanisms. The study was carried out using TGF-ß1-induced BUMPT cells and unilateral ureteral obstruction (UUO)-induced mice, respectively, as in vitro and in vivo models. CircRNA_30032 expression was significantly increased by 9.15- and 16.6-fold on days 3 and 7, respectively, in the renal tissues of UUO model mice. In TGF-ß1-treated BUMPT cells, circRNA_30032 expression was induced by activation of the p38 mitogen-activated protein kinase signaling pathway. Quantitative real-time PCR, western blotting and dual luciferase reporter assays showed that circRNA_30032 mediated TGF-ß1-induced and UUO-induced renal fibrosis by sponging miR-96-5p and increasing the expression of profibrotic proteins, including HBEGF, KRAS, collagen I, collagen III and fibronectin. CircRNA_30032 silencing significantly reduced renal fibrosis in UUO model mice by increasing miR-96-5p levels and decreasing levels of HBEGF and KRAS. These results demonstrate that circRNA_30032 promotes renal fibrosis via the miR-96-5p/HBEGF/KRAS axis and suggest that circRNA_30032 is a potential therapeutic target for treatment of renal fibrosis.


Assuntos
Rim/patologia , MicroRNAs/metabolismo , RNA Circular/metabolismo , Obstrução Ureteral/complicações , Animais , Linhagem Celular , Modelos Animais de Doenças , Células Epiteliais , Fibrose , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Humanos , Rim/citologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Circular/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/genética , Obstrução Ureteral/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Aging (Albany NY) ; 13(9): 12766-12779, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952717

RESUMO

Pain in hepatocellular carcinoma (HCC) is a frequent cause of low quality of life, and morphine is routinely used as a first-line opiate analgesic in HCC. Morphine may exert not only analgesic effects but also anti-cancer effects via unknown mechanisms. Here we show that morphine can inhibit HCC cell proliferation. We further show that DEAD-box helicase 49 (DDX49) is up-regulated in HCC tumors, and that knocking down the DDX49 gene decreases tumor formation in vivo and in vitro, as well as reduces tumor metastasis in vivo. Morphine decreases DDX49 expression in HCC cells. Our results suggest that DDX49 contributes to HCC, and that morphine may exert anti-cancer effects by down-regulating it.


Assuntos
Dor do Câncer/tratamento farmacológico , Carcinoma Hepatocelular/terapia , RNA Helicases DEAD-box/genética , Neoplasias Hepáticas/terapia , Morfina/farmacologia , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Dor do Câncer/etiologia , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Adjuvante/métodos , RNA Helicases DEAD-box/antagonistas & inibidores , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Hepatectomia , Humanos , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Morfina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nat Commun ; 12(1): 2594, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972529

RESUMO

Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.


Assuntos
Células-Tronco Adultas/metabolismo , Ventrículos Laterais/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/genética , Células-Tronco Adultas/citologia , Células-Tronco Adultas/efeitos dos fármacos , Animais , Proteína Morfogenética Óssea 4/farmacologia , Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/genética , Proteínas de Ligação a DNA/metabolismo , Receptores ErbB/farmacologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Ontologia Genética , Imuno-Histoquímica , Interferons/farmacologia , Ventrículos Laterais/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Glicoproteínas de Membrana/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Proteômica , RNA-Seq , Regeneração/efeitos dos fármacos , Tetraspanina 29/metabolismo , Regulação para Cima
18.
PLoS One ; 16(4): e0249059, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33793628

RESUMO

The microenvironment of an early-stage tumor, in which a small number of cancer cells is surrounded by a normal counterpart milieu, plays a crucial role in determining the fate of initiated cells. Here, we examined cell competition between anaplastic thyroid cancer cells and normal thyroid follicular cells using co-culture method. Cancer cells were grown until they formed small clusters, to which normal cells were added to create high-density co-culture condition. We found that co-culture with normal cells significantly suppressed the growth of cancer cell clusters through the activation of Akt-Skp2 pathway. In turn, cancer cells triggered apoptosis in the neighboring normal cells through local activation of ERK1/2. A bi-directional cell competition provides a suppressive mechanism of anaplastic thyroid cancer progression. Since the competitive effect was negated by terminal growth arrest caused by radiation exposure to normal cells, modulation of reciprocal stress response in vivo could be an intrinsic mechanism associated with tumor initiation, propagation, and metastasis.


Assuntos
Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Quinases Associadas a Fase S/genética , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Apoptose/genética , Competição entre as Células/genética , Linhagem Celular Tumoral , Técnicas de Cocultura , Epitélio/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Metástase Neoplásica , Estresse Fisiológico/genética , Carcinoma Anaplásico da Tireoide/patologia , Células Epiteliais da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Microambiente Tumoral/genética
19.
Biochem Biophys Res Commun ; 557: 143-150, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-33865222

RESUMO

Hypoxia-inducible factor 2 (HIF-2), is essential for cellular response to hypoxia and holds an important role in erythropoiesis, angiogenesis, tissue invasion and metastasis, thus, constituting an important therapeutic target. Maximal HIF-2 transcriptional activation requires HIF-2α phosphorylation by ERK1/2 that impairs its CRM1-mediated nuclear export. Herein, we reveal a novel interaction of HIF-2α with Reptin52, a multifunctional protein involved in cellular functions orchestrated both in the nucleus and the cytoplasm. HIF-2α and Reptin52 interact both in nuclear and cytoplasmic fractions, however, ERK1/2 pathway inactivation seems to favour their association in the cytoplasm. Notably, we demonstrate that Reptin52 reduces HIF-2 transcriptional activity, which results in decreased EPO secretion under hypoxia, by impairing HIF-2α stability via a non-canonical PHD-VHL-proteasome independent mechanism. This interaction represents a novel HIF-2 fine tuning mechanism that allows for distinct HIF1/2 isoforms regulation.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Transporte/metabolismo , DNA Helicases/metabolismo , Eritropoetina/metabolismo , Regulação da Expressão Gênica/genética , Sistema de Sinalização das MAP Quinases/genética , ATPases Associadas a Diversas Atividades Celulares/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Transporte/genética , Hipóxia Celular , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromatografia Líquida , Citoplasma/genética , Citoplasma/metabolismo , DNA Helicases/genética , Eritropoese/genética , Eritropoetina/genética , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Espectrometria de Massas em Tandem
20.
Arch Biochem Biophys ; 704: 108885, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33878327

RESUMO

Induction of white fat browning (beiging) and activation of brown fat has been considered a promising strategy to treat obesity and associated metabolic complications. However, the molecular mechanisms regulating brown and beige fat-mediated thermogenesis remains unclear. Our study aimed to identify genes with a hitherto unknown mechanism in the metabolic functions of adipocytes and identified family with sequence similarity 107, member A (FAM107A) as a factor that interferes with fat browning in white adipocytes. We explored physiological roles of FAM107A in cultured 3T3-L1 white adipocytes and HIB1B brown adipocytes by using FAM107A-deficient adipocytes. Significant loss in FAM107A gene functionality induced fat browning was evidenced by evaluating the gene and protein expression level of brown fat-associated markers through real-time qRT-PCR and immunoblot analysis, respectively. Deficiency of FAM107A promoted mitochondrial biogenesis and significantly upregulated core fat-browning marker proteins (PGC-1α, PRDM16, and UCP1) and beige-specific genes (Cd137, Cited1, Tbx1, and Tmem26). Furthermore, FAM107A increased adipogenesis and negatively regulated lipid metabolism in 3T3-L1 adipocytes. In addition, in-silico analysis revealed a strong interaction between FAM107A and ß3-AR based on their energy binding score. Next, mechanistic study revealed that specific knockdown of FAM107A induces browning in white adipocytes via activation of ß3-AR, AMPK and p38 MAPK-dependent signaling pathways. Our data unveiled a previously unknown mechanism of FAM107A in the regulation of lipid metabolism and identified its significant role in metabolic homeostasis. This highlighted the potential of FAM107A as a pharmacotherapeutic target in treating obesity and related metabolic disorders.


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Antígenos de Diferenciação/biossíntese , Regulação da Expressão Gênica , Termogênese , Proteínas Supressoras de Tumor/deficiência , Células 3T3-L1 , Animais , Metabolismo dos Lipídeos/genética , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Proteínas Supressoras de Tumor/metabolismo
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