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1.
Cancer Sci ; 112(3): 1289-1299, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33484209

RESUMO

Tumor angiogenesis is a crucial step in the further growth and metastasis of solid tumors. However, its regulatory mechanism remains unclear. Here, we showed that TARBP2, an RNA-binding protein, played a role in promoting tumor-induced angiogenesis both in vitro and in vivo through degrading the mRNAs of antiangiogenic factors, including thrombospondin1/2 (THBS1/2), tissue inhibitor of metalloproteinases 1 (TIMP1), and serpin family F member 1 (SERPINF1), by targeting their 3'untranslated regions (3'UTRs). Overexpression of TARBP2 promotes tumor cell-induced angiogenesis, while its knockdown inhibits tumor angiogenesis. Clinical cohort analysis revealed that high expression level of TARBP2 was associated with poor survival of lung cancer and breast cancer patients. Mechanistically, TARBP2 physically interacts with the stem-loop structure located in the 3'UTR of antiangiogenic transcripts, leading to mRNA destabilization by the dsRNA-binding domains 1/2 (dsRBDs1/2). Notably, the expression level of TARBP2 in human tumor tissue is negatively correlated with the expression of antiangiogenic factors, including THBS1/2, and brain-specific angiogenesis inhibitor 1 (BAI1). Moreover, TARBP2 expression is strongly associated with tumor angiogenesis in a group of human lung cancer samples. Collectively, our results highlight that TARBP2 is a novel tumor angiogenesis regulator that could promote tumor angiogenesis by selectively downregulating antiangiogenic gene expression.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/patologia , Neovascularização Patológica/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Regiões 3' não Traduzidas/genética , Linhagem Celular Tumoral , Proteínas do Olho/genética , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias/irrigação sanguínea , Neoplasias/genética , Neovascularização Patológica/patologia , Fatores de Crescimento Neural/genética , Estabilidade de RNA/genética , Proteínas de Ligação a RNA/genética , RNA-Seq , Serpinas/genética , Trombospondina 1/genética , Trombospondinas/genética , Inibidor Tecidual de Metaloproteinase-1/genética
2.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498591

RESUMO

The periodontal ligament (PDL) responds to applied orthodontic forces by extracellular matrix (ECM) remodeling, in which human periodontal ligament-derived mesenchymal stromal cells (hPDL-MSCs) are largely involved by producing matrix metalloproteinases (MMPs) and their local inhibitors (TIMPs). Apart from orthodontic forces, the synthesis of MMPs and TIMPs is influenced by the aseptic inflammation occurring during orthodontic treatment. Interleukin (IL)-1ß is one of the most abundant inflammatory mediators in this process and crucially affects the expression of MMPs and TIMPs in the presence of cyclic low-magnitude orthodontic tensile forces. In this study we aimed to investigate, for the first time, how IL-1ß induced expression of MMPs, TIMPs and how IL-1ß in hPDL-MSCs was changed after applying in vitro low-magnitude orthodontic tensile strains in a static application mode. Hence, primary hPDL-MSCs were stimulated with IL-1ß in combination with static tensile strains (STS) with 6% elongation. After 6- and 24 h, MMP-1, MMP-2, TIMP-1 and IL-1ß expression levels were measured. STS alone had no influence on the basal expression of investigated target genes, whereas IL-1ß caused increased expression of these genes. In combination, they increased the gene and protein expression of MMP-1 and the gene expression of MMP-2 after 24 h. After 6 h, STS reduced IL-1ß-induced MMP-1 synthesis and MMP-2 gene expression. IL-1ß-induced TIMP-1 gene expression was decreased by STS after 6- and 24-h. At both time points, the IL-1ß-induced gene expression of IL-1ß was increased. Additionally, this study showed that fetal bovine serum (FBS) caused an overall suppression of IL-1ß-induced expression of MMP-1, MMP-2 and TIMP-1. Further, it caused lower or opposite effects of STS on IL-1ß-induced expression. These observations suggest that low-magnitude orthodontic tensile strains may favor a more inflammatory and destructive response of hPDL-MSCs when using a static application form and that this response is highly influenced by the presence of FBS in vitro.


Assuntos
Interleucina-1beta/farmacologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 2 da Matriz/genética , Células-Tronco Mesenquimais/metabolismo , Ligamento Periodontal/citologia , Estresse Mecânico , Células Cultivadas , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo
3.
Mol Carcinog ; 59(11): 1302-1316, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33006223

RESUMO

Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck. However, the molecular mechanism underlying its development and progression is yet unclear. Genes that are differentially expressed, that is, differentially expressed genes (DEGs), between normal and diseased tissues are believed to be involved in disease development and progression. To identify the DEGs in OSCC and explore their role in occurrence and progression, we established a Chinese hamster OSCC model, determined the DEG, screened the identified DEGs, and performed Gene Ontology (GO) and KEGG enrichment analyses. A protein-protein interaction (PPI) network was generated to screen potential candidate genes. We then analyzed the expression, tumor stage and prognosis of candidate genes using the Gene Expression Profiling Interactive Analysis (GEPIA) database. Finally, we verified the candidate DEGs by quantitative real-time PCR and Gene Expression Omnibus analysis. The results showed 194 significantly DEGs, 140 enriched GO terms, and 8 KEGG pathways, which suggested that OSCC was closely related to the immune system, cell migration, and extracellular matrix. GEPIA and PPI network analysis revealed that SPP1, TNC, and ACTA1 were significantly related to tumor staging; SPP1, tissue inhibitors of matrix metallopeptidases (MMPs) 1 (TIMP1), and ACTA1 were closely related to prognosis. The scores for the top five highest degree genes were close, and the TIMP1/MMP9 axis appeared to be at the center of the PPI network, indicating that expression changes in the TIMP1/MMP9 axis and related genes may be involved in tumor invasion and metastasis. These findings provide novel insights into the mechanism of oral cancer.


Assuntos
Antracenos/toxicidade , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Biologia Computacional/métodos , Modelos Animais de Doenças , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias Bucais/patologia , Piperidinas/toxicidade , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/metabolismo , Proliferação de Células , Cricetinae , Cricetulus , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metaloproteinase 9 da Matriz/genética , Camundongos , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/metabolismo , Prognóstico , Inibidor Tecidual de Metaloproteinase-1/genética , Células Tumorais Cultivadas
4.
Exp Cell Res ; 389(2): 111930, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32113948

RESUMO

Tissue inhibitor of metalloproteinase 1 (TIMP1) has various biological activities including the regulation of cell growth and differentiation. However, its role in bone homeostasis and remodeling remains poorly understood. In this study, we investigate the effects of TIMP1 on osteoblast and osteoclast activity at both cellular and molecular level using siRNA-mediated knockdown technique. Our results show that knockdown of TIMP1 stimulates proliferation and survival, but decreases apoptosis in osteoblastic MC3T3-E1 cells, suggesting that TIMP1 inhibits cell growth. TIMP1 also dampens differentiation of committed osteoblasts, as well as osteoblastogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). We further show that the modulation of TIMP1 on osteoblast activity is independent of its MMP inhibition. Importantly, we uncover that TIMP1 suppresses osteoblast growth and differentiation by targeting the AKT pathway, and this is associated with TIMP1-mediated induction of PTEN via its binding to the cell surface receptor CD44. Therefore, our results highlight a novel TIMP1/CD44/PTEN/AKT signaling nexus that functions as a suppressor of osteoblast activity. Moreover, we show that TIMP1 also inhibits osteoclast differentiation in osteoclast precursor RAW 264.7 cells by targeting the AKT. In conclusion, our results demonstrate that TIMP1 can act as a suppressor of growth and differentiation of osteoblasts and differentiation of osteoclasts through the negative regulation of the AKT pathway. We propose that TIMP1 may serve as a potential target for low bone mass-related skeletal diseases, such as osteoporosis.


Assuntos
Diferenciação Celular , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia , Osteoclastos/citologia , Osteogênese , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Células RAW 264.7 , Inibidor Tecidual de Metaloproteinase-1/genética
5.
Inflamm Res ; 69(4): 423-434, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32144443

RESUMO

OBJECTIVE AND DESIGN: Gallic acid (GA) a naturally occurring phenolic compound, known to possess antioxidant/anti-inflammatory activities. The aim of the present work was to investigate the beneficial effects of GA against COPD-linked lung inflammation/emphysema by utilizing elastase (ET) and cigarette smoke (CS)-induced mice model. MATERIALS: Male BALB/c mice were treated with ET (1U/mouse) or exposed to CS (9 cigarettes/day for 4 days). GA administration was started 7 days (daily) prior to ET/CS exposure. Broncho-alveolar lavage was analyzed for inflammatory cells and pro-inflammatory cytokines. Lung homogenate was assessed for MPO activity/GSH/MDA/protein carbonyls. Further, Lung tissue was subjected to semi-quantitative RT-PCR, immunoblotting, and histological analysis. RESULTS: GA suppressed the ET-induced neutrophil infiltration, elevated MPO activity and production of pro-inflammatory cytokines (IL-6/TNF-α/IL-1ß) at 24 h. Reduced inflammation was accompanied with normalization of redox balance as reflected by ROS/GSH/MDA/protein carbonyl levels. Further, GA suppressed phosphorylation of p65NF-κB and IκBα along with down-regulation of IL-1ß/TNF-α/KC/MIP-2/GCSF genes. Furthermore, GA offered protection against ET-induced airspace enlargement and ameliorated MMP-2/MMP-9. Finally, GA suppressed the CS-induced influx of neutrophils and macrophages and blunted gene expression of TNF-α/MIP-2/KC. CONCLUSION: Overall, our data show that GA effectively modulates pulmonary inflammation and emphysema associated with COPD pathogenesis in mice.


Assuntos
Anti-Inflamatórios/uso terapêutico , Enfisema/tratamento farmacológico , Ácido Gálico/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Enfisema/genética , Enfisema/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Elastase Pancreática , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/imunologia , Fumaça/efeitos adversos , Inibidor Tecidual de Metaloproteinase-1/genética , Tabaco
6.
Int J Mol Sci ; 21(5)2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32150828

RESUMO

High homocysteine is routinely observed in diabetic patients, and this non-protein amino acid is considered as an independent risk factor for diabetic retinopathy. Homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), which is a major methyl donor critical in DNA methylation. Hyperhomocysteinemia is implicated in increased oxidative stress and activation of MMP-9, and in diabetic retinopathy, the activation of MMP-9 facilitates capillary cell apoptosis. Our aim was to investigate the mechanism by which homocysteine activates MMP-9 in diabetic retinopathy. Human retinal endothelial cells, incubated with/without 100 µM homocysteine, were analyzed for MMP-9 and its tissue inhibitor Timp1 expressions and interactions, and ROS levels. Timp1 and MMP-9 promoters were analyzed for methylated and hydroxymethylated cytosine levels (5mC and 5hmC respectively) by the DNA capture method, and DNA- methylating (Dnmt1) and hydroxymethylating enzymes (Tet2) binding by chromatin immunoprecipitation. The results were confirmed in retinal microvessels from diabetic rats receiving homocysteine. Homocysteine supplementation exacerbated hyperglycaemia-induced MMP-9 and ROS levels and decreased Timp1 and its interactions with MMP-9. Homocysteine also aggravated Dnmts and Tets activation, increased 5mC at Timp1 promoter and 5hmC at MMP-9 promoter, and suppressed Timp1 transcription and activated MMP-9 transcription. Similar results were obtained from retinal microvessels from diabetic rats receiving homocysteine. Thus, hyperhomocysteinemia in diabetes activates MMP-9 functionally by reducing Timp1-MMP-9 interactions and transcriptionally by altering DNA methylation-hydroxymethylation of its promoter. The regulation of homocysteine could prevent/slow down the development of retinopathy and prevent their vision loss in diabetic patients.


Assuntos
Metilação de DNA , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/tratamento farmacológico , Regulação da Expressão Gênica , Homocisteína/farmacologia , Metaloproteinase 1 da Matriz/química , Inibidor Tecidual de Metaloproteinase-1/antagonistas & inibidores , Animais , Apoptose , Células Cultivadas , Retinopatia Diabética/etiologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Masculino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo
7.
Proc Natl Acad Sci U S A ; 117(9): 5028-5038, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071226

RESUMO

The brain's endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMRß knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMRß KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.


Assuntos
Astrócitos/metabolismo , Oncostatina M/metabolismo , Remielinização/fisiologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Animais , Astrócitos/patologia , Axônios , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Knockout , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Bainha de Mielina , Células Precursoras de Oligodendrócitos , Inibidor Tecidual de Metaloproteinase-1/genética
8.
Am J Physiol Heart Circ Physiol ; 318(4): H764-H777, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32083975

RESUMO

A variant in the PRDM16 locus has been correlated with QRS duration in an electrocardiogram genome-wide association study, and the deletion of PRDM16 has been implicated as a causal factor of the dilated cardiomyopathy that is linked to 1p36 deletion syndrome. We aimed to determine how a null mutation of Prdm16 affects cardiac function and study the underlying mechanism of the resulting phenotype in an appropriate mouse model. We used cardiac-specific Prdm16 conditional knockout mice to examine cardiac function by electrocardiography. QRS duration and QTc interval increased significantly in cardiac-specific Prdm16 knockout animals compared with wild-type mice. Further, we assessed cardiomyopathy-associated features by trichrome staining, densitometry, and hydroxyproline assay. Prdm16-null hearts showed greater fibrosis and cardiomyocyte hypertrophy. By quantitative real-time PCR, Prdm16-null hearts upregulated extracellular matrix-related genes (Ctgf, Timp1) and α-smooth muscle actin (Acta2), a myofibroblast marker. Moreover, TGF-ß signaling was activated in Prdm16-null hearts, as evidenced by increased Tgfb1-3 transcript levels and phosphorylated Smad2. However, the inhibition of TGF-ß receptor did not reverse the aberrations in conduction in cardiac-specific Prdm16 knockout mice. To determine the underlying mechanisms, we performed RNA-seq using mouse left ventricular tissue. By functional analysis, Prdm16-null hearts experienced dysregulated expression of ion channel genes, including Kcne1, Scn5a, Cacna1h, and Cacna2d2. Mice with Prdm16-null hearts develop abnormalities in cardiac conduction and cardiomyopathy-associated phenotypes, including fibrosis and cellular hypertrophy. Further, the RNA-seq findings suggest that impairments in ion homeostasis (Ca2+, K+, and Na+) may at least partially underlie the abnormal conduction in cardiac-specific Prdm16 knockout mice.NEW & NOTEWORTHY This is the first study that describes aberrant cardiac function and cardiomyopathy-associated phenotypes in an appropriate murine genetic model with cardiomyocyte-specific Prdm16-null mutation. It is noteworthy that the correlation of PRDM16 with QRS duration is replicated in a murine animal model and the potential underlying mechanism may be the impairment of ion homeostasis.


Assuntos
Cardiomiopatias/genética , Proteínas de Ligação a DNA/genética , Frequência Cardíaca , Miócitos Cardíacos/metabolismo , Fenótipo , Fatores de Transcrição/genética , Actinas/genética , Actinas/metabolismo , Animais , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Eletroencefalografia , Fibrose , Canais Iônicos/genética , Canais Iônicos/metabolismo , Masculino , Camundongos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Proteína Smad2/genética , Proteína Smad2/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fatores de Transcrição/metabolismo , Transcriptoma , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
9.
Indian J Pathol Microbiol ; 63(1): 7-12, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32031115

RESUMO

Background: It is well established that chronic exposure to tobacco induces head and neck cancers but the exact etiopathogenesis is not known. Though studies have shown expression of TIMP1, EPS8 and AXL in cancers, their role in tobacco-induced cancers is not known. We aimed this study to evaluate the role of these molecules in oral and oropharyngeal squamous cell cancers (SCC). Materials and Methods: In this single institutional study, 31 patients of oral and oropharyngeal SCC with history of chewing tobacco were included. Smokers were excluded from the study. After informed consent biopsies were taken from affected and contralateral normal mucosa. Paraffin blocks were made and tissue microarray (TMA) were constructed using these blocks. Immunohistochemistry (IHC) for TIMP1, EPS8, AXL kinase was carried out on these tissue microarrays. The intensity of staining was scored from 0 to 3+, related to expression of each of the three molecules. Results: The expression of TIMP1, EPS8 and AXL kinase was significantly more in the cancerous mucosa versus non-cancerous mucosa (P = 0.000 in all three) in oral and oropharyngeal SCC exposed to chewing tobacco. Conclusion: Immunohistochemical expression of these molecular markers in oral and oropharyngeal SCC correlated with their molecular based studies. Significant IHC expression of TIMP1, EPS8 and AXL establishes their role in the pathogenesis of oral and oropharyngeal squamous cell carcinomas. Novel targeted therapies may be researched that can detect and target these molecules at an earlier stage of pathogenesis of these tumors.


Assuntos
Neoplasias Bucais/induzido quimicamente , Neoplasias Orofaríngeas/induzido quimicamente , Tabaco sem Fumaça/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Índia , Masculino , Pessoa de Meia-Idade , Boca/patologia , Neoplasias Bucais/patologia , Neoplasias Orofaríngeas/patologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Centros de Atenção Terciária , Análise Serial de Tecidos , Inibidor Tecidual de Metaloproteinase-1/genética
10.
Chem Biol Interact ; 317: 108945, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31935363

RESUMO

Liver fibrosis is a common pathological consequence of liver injury, which increases liver failure-related morbidity and mortality. Hence, anti-fibrotic treatment is urgently needed. Oxidative stress plays a pivotal role in the progression of liver fibrosis. Thus, targeting ROS may be an effective strategy for liver fibrosis treatment. In this study, we investigated four benzoquinones derivatives, including 5-isopropyl-2-methyl-1,4-benzoquinone (TQ), 2-tert-butyl-1,4-benzoquinone (tBu-Q) 2,5-dimethyl-p-benzoquinone (Dime-Q) and p-benzoquinone (Ph-Q), as well as the evaluation of their antioxidant activity and anti-fibrotic effects on activated hepatic stellate cells and TAA-induced mice. Electrochemical analysis showed that all compounds possessed antioxidant property. The result was first confirmed by in vitro experiments, which revealed potential anti-fibrotic activity of all four compounds at the cellular level. Benzoquinone derivatives act as ROS-scavenging molecules, which modulated the TLR4-CD14 signaling pathway to inhibit the expression of procaspase-1 and IL-1ß in cells, induced apoptosis via a mitochondrial pathway by upregulating the ratio of Bax/Bcl-2 and by activating caspase-3, as well as inhibited the expression of the anti-apoptotic proteins FLIP and XIAP in activated LX-2 cells. In addition, a TAA (Thioacetamide)-induced mouse model was used to further validate the results. Treatment with benzoquinone derivatives significantly decreased the levels of liver injury markers and lipid peroxidation caused by excessive ROS, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA). Moreover, treatment with benzoquinone derivatives significantly inhibited extracellular matrix (ECM) deposition and downregulated the mRNA and protein expression of liver fibrosis markers, such as collagen I, alpha-smooth muscle actin (α-SMA), and TIMP-1. In summary, these results indicate that benzoquinone derivatives may act as potential therapeutic drugs against liver fibrosis.


Assuntos
Antioxidantes/farmacologia , Benzoquinonas/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Tioacetamida/toxicidade , Actinas/genética , Actinas/metabolismo , Animais , Biomarcadores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo
11.
Am J Vet Res ; 81(2): 180-189, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31985291

RESUMO

OBJECTIVE: To characterize transcription of profibrotic mediators in renal tissues of cats with ischemia-induced chronic kidney disease (CKD). SAMPLE: Banked renal tissues from 6 cats with experimentally induced CKD (RI group) and 8 healthy control cats. PROCEDURES: For cats of the RI group, both kidneys were harvested 6 months after ischemia was induced for 90 minutes in 1 kidney. For control cats, the right kidney was evaluated. All kidney specimens were histologically examined for fibrosis, inflammation, and tubular atrophy. Renal tissue homogenates underwent reverse transcription quantitative PCR assay evaluation to characterize gene transcription of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), transforming growth factor-ß1, and vascular endothelial growth factor A. Gene transcription and histologic lesions were compared among ischemic and contralateral kidneys of the RI group and control kidneys. RESULTS: Ischemic kidneys had greater transcript levels of MMP-7, MMP-9, and transforming growth factor-ß1 relative to control kidneys and of MMP-2 relative to contralateral kidneys. Transcription of TIMP-1 was upregulated and that of vascular endothelial growth factor A was downregulated in ischemic and contralateral kidneys relative to control kidneys. Transcription of HIF-1α did not differ among kidney groups. For ischemic kidneys, there were strong positive correlations between transcription of HIF-1α, MMP-2, MMP-7, and TIMP-1 and severity of fibrosis. CONCLUSIONS AND CLINICAL RELEVANCE: Transcription of genes involved in profibrotic pathways remained altered in both kidneys 6 months after transient renal ischemia. This suggested that a single unilateral renal insult can have lasting effects on both kidneys.


Assuntos
Doenças do Gato , Insuficiência Renal Crônica/veterinária , Inibidor Tecidual de Metaloproteinase-1/genética , Transcrição Genética , Animais , Doenças do Gato/genética , Gatos , Rim , Fator A de Crescimento do Endotélio Vascular
12.
Dig Dis Sci ; 65(7): 1971-1979, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31808003

RESUMO

BACKGROUND: The level of interleukin (IL)-17 is commonly increased in serum and intestinal mucosa of patients with inflammatory bowel disease, especially Crohn's disease with intestinal stricture. However, the role of IL-17 in the pathogenesis of intestinal fibrosis and the effect of anti-IL-17 treatment on intestinal fibrosis remain unclear; these issues are studied in vivo in this study. METHOD: A total of 24 wild female Balb/c mice (18-22 g) were randomly divided into three groups: (1) control group, (2) 2,4,6-trinitrobenzenesulfonic acid (TNBS) + immunoglobulin G (IgG) group, and (3) TNBS + anti-IL-17 group. The levels of IL-17, IL-1ß, transforming growth factor (TGF)-ß1, and tumor necrosis factor (TNF)-α in blood and of collagen 3 and IL-17 in gut were measured by enzyme-linked immunosorbent assay (ELISA). The messenger RNA (mRNA) levels of collagen 3, IL-17, TNF-α, tissue inhibitor of metalloproteinase (TIMP)-1, and matrix metalloproteinase (MMP)-2 in gut were measured by reverse-transcription polymerase chain reaction. The protein expression of IL-17, collagen 3, TNF-α, TIMP-1, and MMP-2 were measured by immunoblot analysis. Collagen deposition was evaluated by standard hematoxylin and eosin and Masson's trichrome staining. RESULTS: The profibrogenic cytokines IL-17, IL-1ß, TGF-ß1, and TNF-α in serum, mRNA levels of collagen 3, IL-17, TNF-α, TIMP-1, and MMP-2, and protein levels of IL-17, collagen 3, TNF-α, TIMP-1, and MMP-2 in gut were upregulated in TNBS-induced intestinal fibrosis mice. Treatment with anti-IL-17 antibody significantly alleviated intestinal fibrosis and reduced both mRNA and protein levels of collagen 3, TNF-α, TIMP-1, and MMP-2. The levels of profibrogenic cytokines IL-1ß, TGF-ß1, and TNF-α were also decreased in mice treated with anti-IL-17 antibody. CONCLUSIONS: IL-17 contributes to the pathogenesis of intestinal fibrosis, and anti-IL-17 therapy may weaken this effect by downregulating expression of profibrogenic cytokines and disturbing the MMP/TIMPs balance.


Assuntos
Doença de Crohn/imunologia , Fibrose/imunologia , Interleucina-17/imunologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Animais , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Doença de Crohn/genética , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Modelos Animais de Doenças , Feminino , Fibrose/induzido quimicamente , Fibrose/genética , Fibrose/metabolismo , Imunoglobulina G , Interleucina-17/antagonistas & inibidores , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
13.
Gut ; 69(3): 540-550, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31562239

RESUMO

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose at resectable stage. Recent studies have suggested that extracellular vesicles (EVs) contain long RNAs. The aim of this study was to develop a diagnostic (d-)signature for the detection of PDAC based on EV long RNA (exLR) profiling. DESIGN: We conducted a case-control study with 501 participants, including 284 patients with PDAC, 100 patients with chronic pancreatitis (CP) and 117 healthy subjects. The exLR profile of plasma samples was analysed by exLR sequencing. The d-signature was identified using a support vector machine algorithm and a training cohort (n=188) and was validated using an internal validation cohort (n=135) and an external validation cohort (n=178). RESULTS: We developed a d-signature that comprised eight exLRs, including FGA, KRT19, HIST1H2BK, ITIH2, MARCH2, CLDN1, MAL2 and TIMP1, for PDAC detection. The d-signature showed high accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.960, 0.950 and 0.936 in the training, internal validation and external validation cohort, respectively. The d-signature was able to identify resectable stage I/II cancer with an AUC of 0.949 in the combined three cohorts. In addition, the d-signature showed superior performance to carbohydrate antigen 19-9 in distinguishing PDAC from CP (AUC 0.931 vs 0.873, p=0.028). CONCLUSION: This study is the first to characterise the plasma exLR profile in PDAC and to report an exLR signature for the detection of pancreatic cancer. This signature may improve the prognosis of patients who would have otherwise missed the curative treatment window.


Assuntos
Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/diagnóstico , Vesículas Extracelulares/metabolismo , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/diagnóstico , RNA/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , alfa-Globulinas/genética , Área Sob a Curva , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/genética , Estudos de Casos e Controles , Criança , Claudina-1/genética , Feminino , Fibrinogênio/genética , Humanos , Queratina-19/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas Proteolipídicas Associadas a Linfócitos e Mielina/genética , Neoplasias Pancreáticas/genética , Pancreatite Crônica/sangue , RNA Circular/sangue , RNA Longo não Codificante/sangue , RNA Mensageiro/sangue , Curva ROC , Análise de Sequência de RNA , Máquina de Vetores de Suporte , Inibidor Tecidual de Metaloproteinase-1/genética , Ubiquitina-Proteína Ligases/genética , Adulto Jovem
14.
Minerva Med ; 111(3): 213-225, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31638362

RESUMO

BACKGROUND: Gastric cancer (GC) is the fourth most common cause of cancer-related deaths in the world and 5-year overall survival (OS) rate is less than 10%. So, it is urgent to identified novel diagnostic and prognostic biomarkers. METHODS: Twelve GEO (gene expression omnibus) datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between GC and normal tissues were screened and integrated using limma and RobustRankAggreg (RRA) packages in R software. Protein-protein interaction (PPI) network, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses for DEGs were conducted via STRING and DAVID, respectively. Moreover, Cox regression model was used to construct a gene prognosis signature. RESULTS: Ten genes (COL1A1, CXCL8, COL3A1, SPP1, COL1A2, TIMP1, CXCL1, BGN, MMP3 and SERPINE1) were identified and might be highly related to GC. Further analysis showed high expression of CXCL8, COL3A1, CXCL1, MMP3 and SERPINE1, were significantly associated with late stage of GC. Lastly, we build a seven-gene prognosis signature (CYP19A1, SERPINE1, CGB5, CALCR, ASGR2, CYTL1 and ABCB5), which can give a good prediction of OS. CONCLUSIONS: Our article screened out key genes highly associating with GC's developments and prognosis, and it is useful for researcher to further understand GC's molecular basis and direct the synthesis medicine of GC.


Assuntos
Neoplasias Gástricas/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Aromatase/genética , Receptor de Asialoglicoproteína/genética , Biglicano/genética , Proteínas Sanguíneas/genética , Proteína Semelhante a Receptor de Calcitonina/genética , Quimiocina CXCL1/genética , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Biologia Computacional , Citocinas/genética , Bases de Dados Genéticas , Regulação para Baixo , Expressão Gênica , Humanos , Interleucina-8/genética , Metaloproteinase 3 da Matriz/genética , Osteopontina/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Prognóstico , Análise Serial de Proteínas , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Inibidor Tecidual de Metaloproteinase-1/genética , Regulação para Cima
15.
Br J Biomed Sci ; 77(1): 13-18, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31397194

RESUMO

Introduction: Single nucleotide polymorphisms (SNPs) in genes for certain structural components may be implicated in the pathogenesis of keratoconus. We hypothesized links between SNPs in genes coding for collagen, matrix metalloproteinase 9 (MMP9) and tissue inhibitor of matrix metalloproteinase (TIMP) and keratoconus. Furthermore, we hypothesized links between MMP-9 and TIMP-1 SNPs and their tear level in keratoconus patients.Materials and methods: We genotyped 200 keratoconus and 100 control subjects by allele-specific PCR, and quantified MMP-9 and TIMP1 in tear samples by ELISA.Results: COL4A3 (rs55703767) and MMP-9 (rs17576) G alleles were over-represented in keratoconus patients (P < 0.01). TIMP-1 (rs6609533) A allele was more prevalent in keratoconus females (P < 0.01) but not in males (P = 0.73). MMP-9 was higher (P < 0.001) and TIMP1 lower (P < 0.001) in tear samples from keratoconus patients compared to controls. Keratoconus cases carrying MMP-9 (rs17576) homozygous (GG) alleles had higher tear MMP-9 compared to those carrying the (A) allele (P < 0.01). Females carrying TIMP-1 (rs6609533) homozygous (AA) alleles in both groups had significantly lower tear TIMP-1 compared to carriers of the AG and GG genotypes.Conclusions: This study supports the hypothesis of a functional role for COL4A3 (rs55703767, G/T), MMP-9 (rs17576, A/G) and TIMP-1 (rs6609533, A/G) SNPs in the pathogenesis of keratoconus.


Assuntos
Autoantígenos/genética , Colágeno Tipo IV/genética , Ceratocone/genética , Metaloproteinase 9 da Matriz/genética , Polimorfismo de Nucleotídeo Único/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Adulto , Alelos , Matriz Extracelular , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino
16.
J Ethnopharmacol ; 246: 111768, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30849507

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma wenyujin Y.H. (CW), a variety of Curumae Rhizoma, which documented in China Pharmacopeia, has long been used as plant medicine for its traditional effect on promoting Qi, activating blood stagnation and expelling blood stasis. Nowadays, it is often used in clinic for extraordinary effect on liver diseases. It is worthy to be noted that CW processed with vinegar has been applied in clinic for 1500 years which started in the northern and southern dynasties. AIM OF STUDY: Liver fibrosis is a worldwide clinical issue. It is worth developing a multi-target and multicellular approach which is high efficiency and low side effects for the treatment of hepatic fibrosis. The anti-hepatic fibrosis molecular mechanisms of CW and vinegar Curcuma wenyujin (VCW) need to be explored and elucidated. Furthermore, the study aimed to discuss the efficiency and mechanism differences between CW and VCW in hepatic fibrosis. METHODS AND RESULTS: Biochemical assays and histopathology were adopted to evaluate the anti-hepatic fibrosis effect of CW and VCW. The TGF-ß/Smad signaling involving TGF-ß1, TGF-ßRⅠ, TGF-ßRⅡ and Smad2, Smad3, Smad7 in fibrosis is examined, which is a critical step towards the evaluation of anti-hepatic fibrosis agents. Meanwhile, the MMP/TIMP balance is a potential therapy target by modulating extracellular matrix, which is also examined. Both CW and VCW inhibit the activation and proliferation of hepatic stellate cells and induce apoptosis via blocking TGF-ß/Smad signaling pathways. Additionally, the level of MMP-2/TIMP-1 regulated significantly, which suggest CW and VCW participate in the degradation process, and maintain the formation and production of extracellular matrix. CONCLUSION: Raw and vinegar processed Curcuma wenyujin regulates hepatic fibrosis via bloking TGF-ß/Smad signaling pathways and up-regulation of MMP-2/TIMP-1 ratio. And VCW has more exhibition than CW.


Assuntos
Curcuma , Cirrose Hepática/metabolismo , Extratos Vegetais/farmacologia , Ácido Acético/química , Animais , Linhagem Celular , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
17.
Oncol Res ; 28(3): 225-236, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31796150

RESUMO

S100 binding protein A16 (S100A16) expression levels are closely associated with microRNA (miRNA) processing. Higher levels of S100A16 are reported during the progression of many cancers. Our study mainly explored the interaction between S100A16 and miR-6884-5p in gastric cancer (GC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the level of S100A16 and miR-6884-5p in GC tissues and cell lines. The si-S100A16, pcDNA-S100A16, miR-6884-5p mimic or inhibitor was transfected into GC cells, and the effects of S100A16 and miR-6884-5p on the proliferation, invasion, and epithelial-mesenchymal transition (EMT) were explored by qRT-PCR and Western blot assays. Luciferase assays were performed to validate S100A16 as an miR-6884-5p target in GC cells. In our study, we found that the level of miR-6884-5p was significantly decreased and the expression of S100A16 was significantly increased in GC tissues and cell lines. There was a close association between these changes. Knockdown of S100A16 significantly inhibited the proliferation, invasion, and EMT of GC cells. The bioinformatics analysis predicted that S100A16 is a potential target gene of miR-6884-5p, and the luciferase reporter assay confirmed that miR-6884-5p could directly target S100A16. Introduction of miR-6884-5p to GC cells had similar effects to S100A16 silencing. Overexpression of S100A16 in GC cells partially reversed the inhibitory effects of the miR-6884-5p mimic. miR-6884-5p inhibited the proliferation, invasion, and EMT of GC cells by directly decreasing S100A16 expression.


Assuntos
Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Interferência de RNA , Proteínas S100/genética , Neoplasias Gástricas/genética , Biomarcadores , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo
18.
Int J Mol Sci ; 21(24)2020 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-33419373

RESUMO

Matrix metalloproteinases (MMPs) are a family of zinc-dependent extracellular matrix (ECM) remodeling endopeptidases that have the capacity to degrade almost every component of the ECM. The degradation of the ECM is of great importance, since it is related to embryonic development and angiogenesis. It is also involved in cell repair and the remodeling of tissues. When the expression of MMPs is altered, it can generate the abnormal degradation of the ECM. This is the initial cause of the development of chronic degenerative diseases and vascular complications generated by diabetes. In addition, this process has an association with neurodegeneration and cancer progression. Within the ECM, the tissue inhibitors of MMPs (TIMPs) inhibit the proteolytic activity of MMPs. TIMPs are important regulators of ECM turnover, tissue remodeling, and cellular behavior. Therefore, TIMPs (similar to MMPs) modulate angiogenesis, cell proliferation, and apoptosis. An interruption in the balance between MMPs and TIMPs has been implicated in the pathophysiology and progression of several diseases. This review focuses on the participation of both MMPs (e.g., MMP-2 and MMP-9) and TIMPs (e.g., TIMP-1 and TIMP-3) in physiological processes and on how their abnormal regulation is associated with human diseases. The inclusion of current strategies and mechanisms of MMP inhibition in the development of new therapies targeting MMPs was also considered.


Assuntos
Diabetes Mellitus/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Doença Crônica/prevenção & controle , Diabetes Mellitus/patologia , Matriz Extracelular/genética , Humanos , Metaloproteinases da Matriz/genética , Neovascularização Fisiológica/genética , Inibidor Tecidual de Metaloproteinase-3 , Inibidores Teciduais de Metaloproteinases/genética
19.
Nutrients ; 12(1)2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878149

RESUMO

Orexin-A is a peptide hormone that plays a crucial role in feeding regulation and energy homeostasis. Diurnal intermittent fasting (DIF) has been found to increase orexin-A plasma levels during fasting hours, while Ramadan fasting which resembles DIF, has led to beneficial effects on endothelial function. Herein, we aimed to investigate the effects of orexin-A on the expression of molecules involved in the atherogenesis process: Monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase-1 and 2 (TIMP-1 and TIMP-2), in human aortic endothelial cells (HAECs). HAECs were incubated with orexin-A at concentrations of 40 ng/mL, 200 ng/mL and 400 ng/mL for 6, 12 and 24 h. The mRNA levels of MCP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 and orexin-1 receptor were measured by real-time qPCR. We also evaluated the MMP-2, p38, phospho-p38, NF-κΒ/p65 as well as TIMP-1 protein levels by Western blot and ELISA, respectively. MMP-2 activity was measured by gelatin zymography. Short-term 6-h incubation of HAECs with orexin-A at a high concentration (400 ng/mL) decreased MCP-1, MMP-2 expression, MMP-2/TIMP-1 ratio (p < 0.05), and MMP-2 activity, while incubation for 24 h increased MCP-1, MMP-2 expression (p < 0.05), MMP-2/TIMP-1 and MMP-2/TIMP-2 ratio (p < 0.01 and p < 0.05, respectively) as well as MMP-2 activity. The dual effects of orexin-A are mediated, at least in part, via regulation of p38 and NF-κΒ pathway. Orexin-A may have an equivocal role in atherosclerosis process with its effects depending on the duration of exposure.


Assuntos
Aterosclerose/prevenção & controle , Células Endoteliais/efeitos dos fármacos , Orexinas/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Esquema de Medicação , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Orexinas/administração & dosagem , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo
20.
Cells ; 9(1)2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31861382

RESUMO

Epithelial Ovarian Cancer (EOC) is the most lethal gynecological cancer in developed countries, and the development of new strategies to overcome chemoresistance is an awaited clinical need. Angiogenesis, the development of new blood vessels from pre-existing vasculature, has been validated as a therapeutic target in this tumor type. The aim of this study is to verify if EOC cells with acquired resistance to platinum (PT) treatment display an altered angiogenic potential. Using a proteomic approach, we identified the tissue inhibitor of metalloproteinases 1 (TIMP-1) as the only secreted factor whose expression was up-regulated in PT-resistant TOV-112D and OVSAHO EOC cells used as study models. We report that TIMP-1 acts as a double-edged sword in the EOC microenvironment, directly affecting the response to PT treatment on tumor cells and indirectly altering migration and proliferation of endothelial cells. Interestingly, we found that high TIMP-1 levels in stage III-IV EOC patients associate with decreased overall survival, especially if they were treated with PT or bevacizumab. Taken together, these results pinpoint TIMP-1 as a key molecule involved in the regulation of EOC PT-resistance and progression disclosing the possibility that it could be used as a new biomarker of PT-resistance and/or therapeutic target.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Resistencia a Medicamentos Antineoplásicos , Platina/farmacologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Regulação para Cima , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estadiamento de Neoplasias , Proteômica , Análise de Sobrevida , Microambiente Tumoral
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