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1.
Int Heart J ; 62(5): 1135-1144, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34588407

RESUMO

Myocardial fibrosis is an important pathological phenomenon of cardiac remodeling that is induced by hypertension, myocardial ischemia, valvular heart disease, hypertrophic cardiomyopathy, and other heart diseases and can progress to heart failure. Urotensin II (UII) is regarded as a cardiovascular autacoid/hormone that is not only the most potent vasoconstrictor in mammals but also involved in cardiac remodeling. However, the molecular mechanisms responsible for UII-induced cardiac fibrosis have not yet been fully elucidated. Therefore, we aimed to investigate the effect of UII on myocardial fibrosis in cardiac hypertrophy and the mechanism of UII-induced cardiac fibrosis. Cardiac tissue from mice subjected to Transverse aortic constriction (TAC) was collected. Cardiac hypertrophy, myocardial fibrosis, and the expression of UII protein were assessed using echocardiography and pathological and molecular biological analyses. The effect of UII on fibrosis was evaluated in UII-treated mice and isolated rat primary cardiac fibroblasts, and the results indicated that UII induced significant myocardial fibrosis and increases in the proliferation and fibrotic responses both in mice and cultured fibroblasts. Mechanistically, UII treatment induced activation of the TGF-ß/Smad signaling pathway, which was suppressed by the UII receptor antagonist. In conclusion, UII plays critical roles in cardiac fibrosis by modulating the TGF-ß/Smads signaling pathway, which may be a promising therapeutic target in hypertrophic cardiomyopathy and related problems, such as cardiac remodeling and heart failure.


Assuntos
Cardiomegalia/etiologia , Miocárdio/patologia , Transdução de Sinais , Proteína Smad1/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Urotensinas/efeitos adversos , Animais , Fibrose/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL
2.
Cancer Sci ; 112(10): 4198-4207, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34375482

RESUMO

Tumor-associated macrophages (TAMs), one of the most common cell components in the tumor microenvironment, have been reported as key contributors to cancer-related inflammation and enhanced metastatic progression of tumors. To explore the underlying mechanism of TAM-induced tumor progression, TAMs were isolated from colorectal cancer patients, and the functional interaction with colorectal cancer cells was analyzed. Our study found that coculture of TAMs contributed to a glycolytic state in colorectal cancer, which promoted the stem-like phenotypes and invasion of tumor cells. TAMs produced the cytokine transforming growth factor-ß to support hypoxia-inducible factor 1α (HIF1α) expression, thereby upregulating Tribbles pseudokinase 3 (TRIB3) in tumor cells. Elevated expression of TRIB3 resulted in activation of the ß-catenin/Wnt signaling pathway, which eventually enhanced the stem-like phenotypes and cell invasion in colorectal cancer. Our findings provided evidence that TAMs promoted colorectal cancer progression in a HIF1α/TRIB3-dependent manner, and blockade of HIF1α signals efficiently improved the outcome of chemotherapy, describing an innovative approach for colorectal cancer treatment.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorretais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Macrófagos Associados a Tumor/fisiologia , Animais , Proliferação de Células , Técnicas de Cocultura , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Células HCT116 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Invasividade Neoplásica , Células-Tronco Neoplásicas , Fenótipo , Proteínas Serina-Treonina Quinases/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/metabolismo , Regulação para Cima , Via de Sinalização Wnt/fisiologia
3.
PLoS Genet ; 17(7): e1009678, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34260587

RESUMO

Animals can adapt to dynamic environmental conditions by modulating their developmental programs. Understanding the genetic architecture and molecular mechanisms underlying developmental plasticity in response to changing environments is an important and emerging area of research. Here, we show a novel role of cAMP response element binding protein (CREB)-encoding crh-1 gene in developmental polyphenism of C. elegans. Under conditions that promote normal development in wild-type animals, crh-1 mutants inappropriately form transient pre-dauer (L2d) larvae and express the L2d marker gene. L2d formation in crh-1 mutants is specifically induced by the ascaroside pheromone ascr#5 (asc-ωC3; C3), and crh-1 functions autonomously in the ascr#5-sensing ASI neurons to inhibit L2d formation. Moreover, we find that CRH-1 directly binds upstream of the daf-7 TGF-ß locus and promotes its expression in the ASI neurons. Taken together, these results provide new insight into how animals alter their developmental programs in response to environmental changes.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adaptação Fisiológica/genética , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Ciclo Celular , Processos de Crescimento Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Larva/genética , Larva/crescimento & desenvolvimento , Feromônios/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/fisiologia
4.
Theranostics ; 11(13): 6491-6506, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995670

RESUMO

Rationale: TGFß signaling pathway controls tissue fibrotic remodeling, a hallmark in many diseases leading to organ injury and failure. In this study, we address the role of Apilimod, a pharmacological inhibitor of the lipid kinase PIKfyve, in the regulation of cardiac pathological fibrotic remodeling and TGFß signaling pathway. Methods: The effects of Apilimod treatment on myocardial fibrosis, hypertrophy and cardiac function were assessed in vivo in a mouse model of pressure overload-induced heart failure. Primary cardiac fibroblasts and HeLa cells treated with Apilimod as well as genetic mutation of PIKfyve in mouse embryonic fibroblasts were used as cell models. Results: When administered in vivo, Apilimod reduced myocardial interstitial fibrosis development and prevented left ventricular dysfunction. In vitro, Apilimod controlled TGFß-dependent activation of primary murine cardiac fibroblasts. Mechanistically, both Apilimod and genetic mutation of PIKfyve induced TGFß receptor blockade in intracellular vesicles, negatively modulating its downstream signaling pathway and ultimately dampening TGFß response. Conclusions: Altogether, our findings propose a novel function for PIKfyve in the control of myocardial fibrotic remodeling and the TGFß signaling pathway, therefore opening the way to new therapeutic perspectives to prevent adverse fibrotic remodeling using Apilimod treatment.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Hidrazonas/uso terapêutico , Morfolinas/uso terapêutico , Fosfatidilinositol 3-Quinases/fisiologia , Pirimidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/fisiologia , Animais , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/efeitos dos fármacos , Fibrose , Células HEK293 , Células HeLa , Insuficiência Cardíaca/patologia , Humanos , Hidrazonas/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Miocárdio/patologia , Pirimidinas/farmacologia , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo II/efeitos dos fármacos , Método Simples-Cego , Disfunção Ventricular Esquerda/prevenção & controle , Remodelação Ventricular/efeitos dos fármacos
5.
Theranostics ; 11(13): 6573-6591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995677

RESUMO

Mesenchymal stem cells (MSCs) have been identified in many adult tissues. MSCs can regenerate through cell division or differentiate into adipocytes, osteoblasts and chondrocytes. As a result, MSCs have become an important source of cells in tissue engineering and regenerative medicine for bone tissue and cartilage. Several epigenetic factors are believed to play a role in MSCs differentiation. Among these, microRNA (miRNA) regulation is involved in the fine modulation of gene expression during osteogenic/chondrogenic differentiation. It has been reported that miRNAs are involved in bone homeostasis by modulating osteoblast gene expression. In addition, countless evidence has demonstrated that miRNAs dysregulation is involved in the development of osteoporosis and bone fractures. The deregulation of miRNAs expression has also been associated with several malignancies including bone cancer. In this context, bone-associated circulating miRNAs may be useful biomarkers for determining the predisposition, onset and development of osteoporosis, as well as in clinical applications to improve the diagnosis, follow-up and treatment of cancer and metastases. Overall, this review will provide an overview of how miRNAs activities participate in osteogenic/chondrogenic differentiation, while addressing the role of miRNA regulatory effects on target genes. Finally, the role of miRNAs in pathologies and therapies will be presented.


Assuntos
Doenças Ósseas/genética , Condrogênese/genética , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Osteogênese/genética , Proteínas Morfogenéticas Ósseas/fisiologia , Subunidade alfa 1 de Fator de Ligação ao Core/fisiologia , Sistemas de Liberação de Medicamentos , Fraturas Ósseas/metabolismo , Histona Desacetilases/fisiologia , Humanos , Metaloproteinase 13 da Matriz/fisiologia , Proteínas Repressoras/fisiologia , Transdução de Sinais , Proteínas Smad/fisiologia , Fator de Transcrição Sp7/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia
6.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946990

RESUMO

Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator.


Assuntos
Processamento de Proteína Pós-Traducional/fisiologia , Transdução de Sinais/fisiologia , Proteases Específicas de Ubiquitina/fisiologia , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/fisiologia , Complexo do Signalossomo COP9/fisiologia , Humanos , Imunidade Inata , Masculino , Camundongos , NF-kappa B/metabolismo , Neoplasias da Próstata/metabolismo , Domínios Proteicos , Isoformas de Proteínas , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Precursores de RNA/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Proteases Específicas de Ubiquitina/química , Proteases Específicas de Ubiquitina/genética , Ubiquitinação , Via de Sinalização Wnt/fisiologia , Proteínas de Xenopus/metabolismo
7.
Int J Radiat Oncol Biol Phys ; 111(1): 249-259, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33848608

RESUMO

PURPOSE: Radiation-induced lung injury (RILI) is a progressive condition with an early phase (radiation pneumonitis) and a late phase (lung fibrosis). RILI may occur after partial-body ionizing radiation exposures or internal radioisotope exposure, with wide individual variability in timing and extent of lung injury. This study aimed to provide new insights into the pathogenesis and progression of RILI in the nonhuman primate (NHP) rhesus macaque model. METHODS AND MATERIALS: We used an integrative approach to understand RILI and its evolution at clinical and molecular levels in 17 NHPs exposed to 10 Gy of whole-thorax irradiation in comparison with 3 sham-irradiated control NHPs. Clinically, we monitored respiratory rates, computed tomography (CT) scans, plasma cytokine levels, and bronchoalveolar lavage (BAL) over 8 months and lung samples collected at necropsy for molecular and histopathologic analyses using RNA sequencing and immunohistochemistry. RESULTS: Elevated respiratory rates, greater CT density, and more severe pneumonitis with increased macrophage content were associated with early mortality. Radiation-induced lung fibrosis included polarization of macrophages toward the M2-like phenotype, TGF-ß signaling, expression of CDKN1A/p21 in epithelial cells, and expression of α-SMA in lung stroma. RNA sequencing analysis of lung tissue revealed SERPINA3, ATP12A, GJB2, CLDN10, TOX3, and LPA as top dysregulated transcripts in irradiated animals. In addition to transcriptomic data, we observed increased protein expression of SERPINA3, TGF-ß1, CCL2, and CCL11 in BAL and plasma samples. CONCLUSIONS: Our combined clinical, imaging, histologic, and transcriptomic analysis provides new insights into the early and late phases of RILI and highlights possible biomarkers and potential therapeutic targets of RILI. Activation of TGF-ß and macrophage polarization appear to be key mechanisms involved in RILI.


Assuntos
Perfilação da Expressão Gênica , Lesão Pulmonar/etiologia , Lesões Experimentais por Radiação/etiologia , Animais , Pontos de Checagem do Ciclo Celular , Citocinas/sangue , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Macaca mulatta , Macrófagos/fisiologia , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , Lesões Experimentais por Radiação/diagnóstico por imagem , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Pneumonite por Radiação/etiologia , Pneumonite por Radiação/patologia , Tomografia Computadorizada por Raios X , Fator de Crescimento Transformador beta/fisiologia
8.
Front Immunol ; 12: 645850, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815404

RESUMO

Cytokines are soluble and membrane-bound factors that dictate immune responses. Dogmatically, cytokines are divided into families that promote type 1 cell-mediated immune responses (e.g., IL-12) or type 2 humoral responses (e.g., IL-4), each capable of antagonizing the opposing family of cytokines. The discovery of additional families of cytokines (e.g., IL-17) has added complexity to this model, but it was the realization that immune responses frequently comprise mixtures of different types of cytokines that dismantled this black-and-white paradigm. In some cases, one type of response may dominate these mixed milieus in disease pathogenesis and thereby present a clear therapeutic target. Alternatively, synergistic or blended cytokine responses may obfuscate the origins of disease and perplex clinical decision making. Most immune cells express receptors for many types of cytokines and can mediate a myriad of functions important for tolerance, immunity, tissue damage, and repair. In this review, we will describe the unconventional effects of a variety of cytokines on the activity of a prototypical type 1 effector, the natural killer (NK) cell, and discuss how this may impact the contributions of these cells to health and disease.


Assuntos
Citocinas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Viroses/imunologia , Humanos , Interleucinas/farmacologia , Células Matadoras Naturais/imunologia , Fator de Crescimento Transformador beta/fisiologia
9.
Commun Biol ; 4(1): 290, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33674719

RESUMO

SARS-CoV-2 virus has infected more than 92 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Using a rhesus macaque model of SARS-CoV-2 infection, we have characterized the transcriptional signatures induced in the lungs of juvenile and old macaques following infection. Genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated, as also seen in lungs of macaques with tuberculosis. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. Together, our transcriptomic studies have delineated disease pathways that improve our understanding of the immunopathogenesis of COVID-19.


Assuntos
COVID-19/imunologia , Degranulação Celular , Interferons/fisiologia , Neutrófilos/fisiologia , SARS-CoV-2 , Idoso , Animais , Antígenos CD36/fisiologia , COVID-19/etiologia , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Pulmão/metabolismo , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Receptores Notch/fisiologia , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/fisiologia
11.
Clin Exp Metastasis ; 38(2): 139-161, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33590419

RESUMO

Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. Late-stage diagnosis with significant tumor burden, accompanied by recurrence and chemotherapy resistance, contributes to this poor prognosis. These morbidities are known to be tied to events associated with epithelial-mesenchymal transition (EMT) in cancer. During EMT, localized tumor cells alter their polarity, cell-cell junctions, cell-matrix interactions, acquire motility and invasiveness and an exaggerated potential for metastatic spread. Key triggers for EMT include the Transforming Growth Factor-ß (TGFß) family of growth factors which are actively produced by a wide array of cell types within a specific tumor and metastatic environment. Although TGFß can act as either a tumor suppressor or promoter in cancer, TGFß exhibits its pro-tumorigenic functions at least in part via EMT. TGFß regulates EMT both at the transcriptional and post-transcriptional levels as outlined here. Despite recent advances in TGFß based therapeutics, limited progress has been seen for ovarian cancers that are in much need of new therapeutic strategies. Here, we summarize and discuss several recent insights into the underlying signaling mechanisms of the TGFß isoforms in EMT in the unique metastatic environment of EOCs and the current therapeutic interventions that may be relevant.


Assuntos
Carcinoma Epitelial do Ovário/patologia , Neoplasias Ovarianas/patologia , Fator de Crescimento Transformador beta/fisiologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Metástase Neoplásica , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais/fisiologia , Proteínas Smad/fisiologia , Fator de Crescimento Transformador beta/antagonistas & inibidores
12.
Clin Exp Metastasis ; 38(2): 119-138, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33591548

RESUMO

Cancer is a complex disease, with various pre-existing health ailments enhancing its pathology. In cancer, the extracellular environment contains various intrinsic physiological factors whose levels are altered with aging and pre-existing conditions. In obesity, the tumor microenvironment and metastases are enriched with factors that are both derived locally, and from other physiological compartments. Similarly, in obesity, the cancer cell environment both at the site of origin and at the secondary site i.e., metastatic niche, contains significantly more phenotypically-altered adipocytes than that of un-obese cancer patients. Indeed, obesity has been linked with cancer progression, metastasis, and therapy resistance. Adipocytes not only interact with tumor cells, but also with adjacent stromal cells at primary and metastatic sites. This review emphasizes the importance of bidirectional interactions between adipocytes and breast tumor cells in breast cancer progression and its bone metastases. This paper not only chronicles the role of various adipocyte-derived factors in tumor growth, but also describes the significance of adipocyte-derived bone metastatic factors in the development of bone metastasis of breast cancer. It provides a molecular view of the interplay between the adipocytes and tumor cells involved in breast cancer bone metastasis. However, more research is needed to determine if targeting cancer-associated adipocytes holds promise as a potential therapeutic approach for breast cancer bone metastasis treatment. Interplay between adipocytes and breast cancer cells at primary cancer site and metastatic bone microenvironment. AMSC Adipose-derived mesenchymal stem cell, CAA Cancer associated adipocytes, CAF Cancer associated fibroblast, BMSC Bone marrow derived mesenchymal stem cell, BMA Bone marrow adipocyte.


Assuntos
Adiposidade/fisiologia , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Adiponectina/fisiologia , Estrogênios/fisiologia , Feminino , Humanos , Lipólise , Células-Tronco Mesenquimais/fisiologia , Ligante RANK/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Microambiente Tumoral/fisiologia
13.
Med Sci Monit ; 27: e928813, 2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33619241

RESUMO

BACKGROUND Aminoacylase 1 (ACY-1) is a cytosolic enzyme that catalyzes amino acid deacylation and has been reported to participate in various human diseases. However, the role and mechanism of ACY-1 in neuroblastoma (NB) are not completely understood. The aim of this study was to elucidate the role of ACY-1 in NB. MATERIAL AND METHODS Overexpression and knockdown of ACY-1 in human NB cells were performed, and the transfection efficiency was assessed through fluorescence microscopy, real-time PCR, and western blotting. The effect of ACY-1 on tumorigenesis and metastasis was determined by cell counting, colony formation, wound healing, flow cytometry, and transwell invasion assays in vitro, and the signaling pathway was examined using western blotting. RESULTS ACY-1 overexpression inhibited proliferation and induced apoptosis in human NB cells. ACY-1 inhibited the colony formation ability, migration, and invasion of SH-SY5Y cell lines. Moreover, the ERK1/2 and TGF-ß1 signaling pathways were more active when ACY-1 was overexpressed in NB cells. However, the knockdown of ACY-1 in SH-SY5Y cell lines showed the opposite effects. CONCLUSIONS ACY-1 regulates the proliferation, migration, and invasion of human NB cells through the ERK1/2 and TGF-ß1 signaling pathways, implying that ACY-1 may serve as a therapeutic target for patients with NB.


Assuntos
Amidoidrolases/metabolismo , Neuroblastoma/metabolismo , Amidoidrolases/genética , Apoptose/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Transfecção , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/fisiologia
14.
Int J Mol Sci ; 22(2)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33478130

RESUMO

Autocrine signaling is defined as the production and secretion of an extracellular mediator by a cell followed by the binding of that mediator to receptors on the same cell to initiate signaling. Autocrine stimulation often operates in autocrine loops, a type of interaction, in which a cell produces a mediator, for which it has receptors, that upon activation promotes expression of the same mediator, allowing the cell to repeatedly autostimulate itself (positive feedback) or balance its expression via regulation of a second factor that provides negative feedback. Autocrine signaling loops with positive or negative feedback are an important feature in cancer, where they enable context-dependent cell signaling in the regulation of growth, survival, and cell motility. A growth factor that is intimately involved in tumor development and progression and often produced by the cancer cells in an autocrine manner is transforming growth factor-ß (TGF-ß). This review surveys the many observations of autocrine TGF-ß signaling in tumor biology, including data from cell culture and animal models as well as from patients. We also provide the reader with a critical discussion on the various experimental approaches employed to identify and prove the involvement of autocrine TGF-ß in a given cellular response.


Assuntos
Comunicação Autócrina , Neoplasias/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Animais , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/fisiologia , Pesquisa Biomédica/métodos , Pesquisa Biomédica/normas , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Projetos de Pesquisa , Fator de Crescimento Transformador beta/farmacologia
15.
Int J Cancer ; 148(5): 1245-1259, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152121

RESUMO

Tumour stromal cells support tumourigenesis. We report that Syndecan-2 (SDC2) is expressed on a nonepithelial, nonhaematopoietic, nonendothelial stromal cell population within breast cancer tissue. In vitro, syndecan-2 modulated TGFß signalling (SMAD7, PAI-1), migration and immunosuppression of patient-derived tumour-associated stromal cells (TASCs). In an orthotopic immunocompromised breast cancer model, overexpression of syndecan-2 in TASCs significantly enhanced TGFß signalling (SMAD7, PAI-1), tumour growth and metastasis, whereas reducing levels of SDC2 in TASCs attenuated TGFß signalling (SMAD7, PAI-1, CXCR4), tumour growth and metastasis. To explore the potential for therapeutic application, a syndecan-2-peptide was generated that inhibited the migratory and immunosuppressive properties of TASCs in association with reduced expression of TGFß-regulated immunosuppressive genes, such as CXCR4 and PD-L1. Moreover, using an orthotopic syngeneic breast cancer model, overexpression of syndecan-2-peptide in TASCs reduced tumour growth and immunosuppression within the TME. These data provide evidence that targeting stromal syndecan-2 within the TME inhibits tumour growth and metastasis due to decreased TGFß signalling and increased immune control.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Evasão da Resposta Imune , Sindecana-2/antagonistas & inibidores , Animais , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/fisiologia , Sindecana-2/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Microambiente Tumoral
16.
Gastroenterology ; 160(1): 245-259, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32941878

RESUMO

BACKGROUND & AIMS: Mutations in the APC gene and other genes in the Wnt signaling pathway contribute to development of colorectal carcinomas. R-spondins (RSPOs) are secreted proteins that amplify Wnt signaling in intestinal stem cells. Alterations in RSPO genes have been identified in human colorectal tumors. We studied the effects of RSPO1 overexpression in ApcMin/+ mutant mice. METHODS: An adeno associated viral vector encoding RSPO1-Fc fusion protein, or control vector, was injected into ApcMin/+mice. Their intestinal crypts were isolated and cultured as organoids. which were incubated with or without RSPO1-Fc and an inhibitor of transforming growth factor beta receptor (TGFBR). Livers were collected from mice and analyzed by immunohistochemistry. Organoids and adenomas were analyzed by quantitative reverse-transcription PCR, single cell RNA sequencing, and immunohistochemistry. RESULTS: Intestines from Apc+/+ mice injected with the vector encoding RSPO1-Fc had significantly deeper crypts, longer villi, with increased EdU labeling, indicating increased proliferation of epithelial cells, in comparison to mice given control vector. AAV-RSPO1-Fc-transduced ApcMin/+ mice also developed fewer and smaller intestinal tumors and had significantly longer survival times. Adenomas of ApcMin/+ mice injected with the RSPO1-Fc vector showed a rapid increase in apoptosis and in the expression of Wnt target genes, followed by reduced expression of messenger RNAs and proteins regulated by the Wnt pathway, reduced cell proliferation, and less crypt branching than adenomas of mice given the control vector. Addition of RSPO1 reduced the number of adenoma organoids derived from ApcMin/+ mice and suppressed expression of Wnt target genes but increased phosphorylation of SMAD2 and transcription of genes regulated by SMAD. Inhibition of TGFBR signaling in organoids stimulated with RSPO1-Fc restored organoid formation and expression of genes regulated by Wnt. The TGFBR inhibitor restored apoptosis in adenomas from ApcMin/+ mice expressing RSPO1-Fc back to the same level as in the adenomas from mice given the control vector. CONCLUSIONS: Expression of RSPO1 in ApcMin/+ mice increases apoptosis and reduces proliferation and Wnt signaling in adenoma cells, resulting in development of fewer and smaller intestinal tumors and longer mouse survival. Addition of RSPO1 to organoids derived from adenomas inhibits their growth and promotes proliferation of intestinal stem cells that retain the APC protein; these effects are reversed by TGFB inhibitor. Strategies to increase the expression of RSPO1 might be developed for the treatment of intestinal adenomas.


Assuntos
Adenoma/patologia , Neoplasias Intestinais/patologia , Trombospondinas/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Via de Sinalização Wnt/fisiologia , Adenoma/etiologia , Animais , Modelos Animais de Doenças , Neoplasias Intestinais/etiologia , Camundongos , Organoides
18.
Nucleic Acids Res ; 49(1): 127-144, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33305319

RESUMO

MicroRNAs are regulators of gene expression. A wide-spread, yet not validated, assumption is that the targetome of miRNAs is non-randomly distributed across the transcriptome and that targets share functional pathways. We developed a computational and experimental strategy termed high-throughput miRNA interaction reporter assay (HiTmIR) to facilitate the validation of target pathways. First, targets and target pathways are predicted and prioritized by computational means to increase the specificity and positive predictive value. Second, the novel webtool miRTaH facilitates guided designs of reporter assay constructs at scale. Third, automated and standardized reporter assays are performed. We evaluated HiTmIR using miR-34a-5p, for which TNF- and TGFB-signaling, and Parkinson's Disease (PD)-related categories were identified and repeated the pipeline for miR-7-5p. HiTmIR validated 58.9% of the target genes for miR-34a-5p and 46.7% for miR-7-5p. We confirmed the targeting by measuring the endogenous protein levels of targets in a neuronal cell model. The standardized positive and negative targets are collected in the new miRATBase database, representing a resource for training, or benchmarking new target predictors. Applied to 88 target predictors with different confidence scores, TargetScan 7.2 and miRanda outperformed other tools. Our experiments demonstrate the efficiency of HiTmIR and provide evidence for an orchestrated miRNA-gene targeting.


Assuntos
Regulação da Expressão Gênica/genética , Ensaios de Triagem em Larga Escala , MicroRNAs/genética , 1-Metil-4-fenilpiridínio , Regiões 3' não Traduzidas , Linhagem Celular , Linhagem Celular Tumoral , Genes Reporter , Humanos , Mesencéfalo/citologia , Neuroblastoma/patologia , Neurônios/metabolismo , Doença de Parkinson/genética , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Transdução de Sinais , Transcriptoma , Fator de Crescimento Transformador beta/fisiologia , Fator de Necrose Tumoral alfa/fisiologia
19.
Curr Opin Nephrol Hypertens ; 30(1): 115-122, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33229911

RESUMO

PURPOSE OF REVIEW: Diabetic kidney disease (DKD) is a leading cause of mortality and morbidity in diabetes. This review aims to discuss the major features of DKD, to identify the difficult barrier encountered in developing a therapeutic strategy and to provide a potentially superior novel approach to retard DKD. RECENT FINDINGS: Renal inflammation and fibrosis are prominent features of DKD. Transforming growth factor beta (TGFß) with its activity enhanced in DKD plays a key pathological profibrotic role in promoting renal fibrosis. However, TGFß is a difficult drug target because it has multiple important physiological functions, such as immunomodulation. These physiological functions of TGFß can be interrupted as a result of complete blockade of the TGFß pathway if TGFß is directly targeted, leading to catastrophic side-effects, such as fulminant inflammation. Cell division autoantigen 1 (CDA1) is recently identified as an enhancer of profibrotic TGFß signaling and inhibitor of anti-inflammatory SIRT1. Renal CDA1 expression is elevated in human DKD as well as in rodent models of DKD. Targeting CDA1, by either genetic approach or pharmacological approach in mice, leads to concurrent attenuation of renal fibrosis and inflammation without any deleterious effects observed. SUMMARY: Targeting CDA1, instead of directly targeting TGFß, represents a superior approach to retard DKD.


Assuntos
Autoantígenos , Nefropatias Diabéticas , Rim , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Autoantígenos/genética , Autoantígenos/metabolismo , Citocinas/efeitos adversos , Citocinas/fisiologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Fibrose/tratamento farmacológico , Fibrose/patologia , Fibrose/fisiopatologia , Fibrose/prevenção & controle , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/fisiopatologia , Inflamação/prevenção & controle , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Camundongos , Substâncias Protetoras/uso terapêutico , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/fisiologia
20.
Endocrinology ; 162(3)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33349851

RESUMO

Pancreatic islet beta cells (ß-cells) synthesize and secrete insulin in response to rising glucose levels and thus are a prime target in both major forms of diabetes. Type 1 diabetes ensues due to autoimmune destruction of ß-cells. On the other hand, the prevailing insulin resistance and hyperglycemia in type 2 diabetes (T2D) elicits a compensatory response from ß-cells that involves increases in ß-cell mass and function. However, the sustained metabolic stress results in ß-cell failure, characterized by severe ß-cell dysfunction and loss of ß-cell mass. Dynamic changes to ß-cell mass also occur during pancreatic development that involves extensive growth and morphogenesis. These orchestrated events are triggered by multiple signaling pathways, including those representing the transforming growth factor ß (TGF-ß) superfamily. TGF-ß pathway ligands play important roles during endocrine pancreas development, ß-cell proliferation, differentiation, and apoptosis. Furthermore, new findings are suggestive of TGF-ß's role in regulation of adult ß-cell mass and function. Collectively, these findings support the therapeutic utility of targeting TGF-ß in diabetes. Summarizing the role of the various TGF-ß pathway ligands in ß-cell development, growth and function in normal physiology, and during diabetes pathogenesis is the topic of this mini-review.


Assuntos
Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/crescimento & desenvolvimento , Fator de Crescimento Transformador beta/fisiologia , Animais , Diferenciação Celular/genética , Proliferação de Células/genética , Humanos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/fisiologia , Organogênese/genética , Transdução de Sinais/fisiologia
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