RESUMO
BACKGROUND: Matrix metalloproteinase (MMP)1, MMP9, MMP11, and MMP13 are overexpressed in malignant melanoma (MM), being associated with tumor invasive phase, metastases, and more aggressive neoplastic phenotypes. AIM: The main objective of the current study was to correlate the expression of the MMPs with the evolution of MM toward distant metastasis. PATIENTS, MATERIALS AND METHODS: We designed a retrospective cohort study, including 13 patients with metastatic MM. Data concerning age, sex, localization of the primary lesion and metastasis, and histological and immunohistochemical features (intensity of expression and percent of positive cells for MMPs) were statistically processed. RESULTS: The time between the diagnosis of primitive melanoma and the diagnosis of metastasis ranged between 0 and 73 months, with a mean value of 18.3 months. The metastases rich in MMP1- and MMP9-positive cells occurred earlier than the metastases with low levels of positive cells. The mean period until metastasis was shorter for the MMP1-expressing tumors than the ones without MMP1 expression. MMP13 expression in the tumor and its metastasis was significantly linked with the time until the metastasis occurrence. CONCLUSIONS: This study emphasizes the roles of MMP1, MMP9, and MMP13 in the process of metastasis in melanoma and the opportunity to use them as therapeutic targets and surveillance molecules.
Assuntos
Metaloproteinase 13 da Matriz , Metaloproteinase 1 da Matriz , Metaloproteinase 9 da Matriz , Melanoma , Humanos , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Melanoma/genética , Melanoma/metabolismo , Estudos RetrospectivosRESUMO
BACKGROUND: Matrix metalloproteinases (MMP) are important proteases that degrade the extracellular matrix (ECM) and thus essentially mediate tumor vascularization, metastasis, and invasion. However, their potential roles in uterine corpus endometrial carcinoma (UCEC) are not fully understood. PATIENTS AND METHODS: The expression, prognostic value, and correlation of UCEC patients with MMP were investigated using data from The Cancer Genome Atlas (TCGA) and other databases. Furthermore, differentially expressed genes (DEGs) were identified and their biological functions and correlations with infiltrating immune cells were analyzed. RESULTS: A total of 22 MMPs were found to be abnormally expressed in UCEC tumor tissues, and high expression of MMP11 and MMP17 were associated with a better UCEC prognosis. MMP11 and MMP17 were observed to be significantly enriched in tumor tissue ECM and were associated with pathways involving degradation, glycolytic metabolism, and PI3K-Akt signaling. Infiltration of natural killer (NK), mast, and NK CD56bright cells was enhanced in tumor tissues with high MMP11 and MMP17 expression. CONCLUSION: MMP11 and MMP17 may affect UCEC prognosis by influencing immune cell infiltration and may be potential UCEC biomarkers.
Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , Metaloproteinase 17 da Matriz , Humanos , Feminino , Metaloproteinase 11 da Matriz/genética , Fosfatidilinositol 3-Quinases , Prognóstico , Biomarcadores , Neoplasias do Endométrio/genéticaRESUMO
BACKGROUND: Irisin, a myokine derived from proteolytic cleavage of the fibronectin type III domain-containing protein 5 (FNDC5) protein, is crucial in protecting tissues and organs from ischemia-reperfusion (I/R) injury. However, the underlying mechanism of its action remains elusive. In this study, we investigated the expression patterns of genes associated with FNDC5 knockout to gain insights into its molecular functions. METHODS: We employed a mouse model of skeletal muscle I/R injury with FNDC5 knockout to examine the transcriptional profiles using RNA sequencing. Differentially expressed genes (DEGs) were identified and subjected to further analyses, including gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction (PPI) network analysis, and miRNA-transcription factor network analysis. The bioinformatics findings were validated using qRT-PCR and Western blotting. RESULTS: Comparative analysis of skeletal muscle transcriptomes between wild-type (WT; C57BL/6), WT-I/R, FNDC5 knockout (KO), and KO-I/R mice highlighted the significance of FNDC5 in both physiological conditions and I/R injury. Through PPI network analysis, we identified seven key genes (Col6a2, Acta2, Col4a5, Fap, Enpep, Mmp11, and Fosl1), which facilitated the construction of a TF-hub genes-miRNA regulatory network. Additionally, our results suggested that the PI3K-Akt pathway is predominantly involved in FNDC5 deletion-mediated I/R injury in skeletal muscle. Animal studies revealed reduced FNDC5 expression in skeletal muscle following I/R injury, and the gastrocnemius muscle with FNDC5 knockout exhibited larger infarct size and more severe tissue damage after I/R. Moreover, Western blot analysis confirmed the upregulation of Col6a2, Enpep, and Mmp11 protein levels following I/R, particularly in the KO-I/R group. Furthermore, FNDC5 deletion inhibited the PI3K-Akt signaling pathway. CONCLUSION: This study demonstrates that FNDC5 deletion exacerbates skeletal muscle I/R injury, potentially involving the upregulation of Col6a2, Enpep, and Mmp11. Additionally, the findings suggest the involvement of the PI3K-Akt pathway in FNDC5 deletion-mediated skeletal muscle I/R injury, providing novel insights into the molecular mechanisms underlying FNDC5's role in this pathological process.
Assuntos
MicroRNAs , Traumatismo por Reperfusão , Camundongos , Animais , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Transcriptoma , Fibronectinas/genética , Fibronectinas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Fatores de Transcrição/metabolismo , Traumatismo por Reperfusão/metabolismo , Reperfusão , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.
Assuntos
Neoplasias Colorretais , Mutação com Ganho de Função , Humanos , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Neoplasias Colorretais/patologia , Carcinogênese , Células Germinativas/metabolismoRESUMO
BACKGROUND: Whether pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes exist in gastric cancer (GC) remains unclear. METHODS: Seven independent cohorts including a total of 1901 GC patients were enrolled in our research. TCGA (n = 371) and GSE84437 (n = 433) were combined into one cohort (n = 804) to screen for prognosis-related PAN genes using a univariate Cox regression analysis. The R package "ConsensusClusterPlus" was applied to conduct a clustering analysis of the combination set based on prognosis-related PAN genes. The R package "limma" was used for the identification of differentially expressed genes (DEGs) between different PAN clusters (FDR <0.05 and |logFC|>1). The combined cohort was randomly divided into a training group (n = 484) and a test group (n = 320) at a ratio of 6:4 to establish and verify the prognostic model. A univariate Cox regression analysis, least absolute shrinkage and selection operator method (LASSO) regression analysis, and multivariate Cox regression analysis were used for the identification of prognostic genes and the construction of risk scores. Another five independent cohorts (GSE62254, n = 300; GSE15459, n = 191; GSE26901, n = 109; GSE26253, n = 432; and GSE13861, n = 65) were used for external validation to verify the accuracy and stability of the prognostic signature. RESULTS: The internal and external validation demonstrated that the 5-gene risk score (LOXL4, SLCO2A1, CST2, PDK4, and MMP11) was an effective instrument for the prognostic risk classification of GC patients. The overall survival (OS) and relapse-free survival (RFS) in the high-risk group were significantly lower than those in the low-risk group and were accompanied by a larger proportion of macrophage and regulatory T cell infiltration. The low-risk group had a good prognosis, with a high tumor mutation burden (TMB), strong cytolytic activity, and a higher proportion of activated CD4 T cell infiltration. In addition, compared with the low-risk group, the cancer-related pathways in the high-risk group were overactivated, and the function of DNA damage repair (DDR) was significantly weakened. Regarding drug sensitivity, the high-risk group was more suitable for targeted drugs, such as axitinib, lapatinib, and nilotinib. The low-risk group was more sensitive to chemotherapy, such as cisplatin, gemcitabine, and vinorelbine. CONCLUSION: A universally applicable prognostic signature of GC is proposed in this research based on pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes.
Assuntos
Transportadores de Ânions Orgânicos , Neoplasias Gástricas , Apoptose/genética , Axitinibe , Cisplatino , Perfilação da Expressão Gênica , Humanos , Lapatinib , Metaloproteinase 11 da Matriz/genética , Necroptose/genética , Transportadores de Ânions Orgânicos/genética , Prognóstico , Proteína-Lisina 6-Oxidase , Piroptose/genética , Neoplasias Gástricas/genética , VinorelbinaRESUMO
Breast cancer is the leading cause of cancer death in woman and tremendous efforts are undertaken to limit its dissemination and to provide effective treatment. Various histopathological parameters are routinely assessed in breast cancer biopsies to provide valuable diagnostic and prognostic information. MMP-11 and CD45 are tumor-associated antigens and potentially valuable biomarkers for grading aggressiveness and metastatic probability. This paper presents methods for quantitative and multiplexed imaging of MMP-11 and CD45 in breast cancer tissues and investigates their potential for improved cancer characterization and patient stratification. An immunohistochemistry-assisted laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method was successfully developed and optimized using lanthanide-tagged monoclonal antibodies as proxies to determine spatial distributions and concentrations of the two breast cancer biomarkers. The labeling degree of antibodies was determined via size exclusion-ICP-tandem mass spectrometry (SEC-ICP-MS/MS) employing online calibration via post-column isotope dilution analysis (IDA). The calibration of spatial distributions of labeled lanthanides in tissues was performed by ablating mold-prepared gelatin standards spiked with element standards. Knowledge of labeling degrees enabled the translation of lanthanide concentrations into biomarkers concentrations. The k-means clustering was used to select tissue areas for statistical analysis and mean concentrations were compared for sets of metastatic, non-metastatic and healthy samples. MMP-11 was expressed in stroma surrounding tumor areas, while CD45 was predominantly found inside tumor areas with high cell density. There was no significant correlation between CD45 and metastasis (P = 0.70); however, MMP-11 was significantly up-regulated (202%) in metastatic samples compared to non-metastatic (P = 0.0077) and healthy tissues (P = 0.0087).
Assuntos
Neoplasias da Mama , Antígenos Comuns de Leucócito , Espectrometria de Massas , Metaloproteinase 11 da Matriz , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Elementos da Série dos Lantanídeos/química , Lasers , Antígenos Comuns de Leucócito/análise , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Espectrometria de Massas/métodos , Metaloproteinase 11 da Matriz/análise , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Espectrometria de Massas em TandemRESUMO
Brachydin C (BrC) has demonstrated in vitro cytotoxic and antiproliferative effects in prostate cancer cells. In the present study, we compare the anticancer effects of BrC in DU145 cells grown in common bidimensional cultures (2D) and multicellular tumor spheroids (MCTS), often denominated 3D in vitro models, that can better mimic the microenvironment of tissues. BrC IC50 values obtained in the resazurin assay after 24 h of treatment were 47.31 µM (2D) and 229.8 µM (3D) and these cytotoxic effects were time-dependent only in 3D. BrC (5.0-60 µM) interfered with the growth of MCTS and reduced cell viability after 11 days of treatment, a result that is not attributable to oxidative stress evaluated using the CM-H2 DCFDA probe. BrC (6.0 µM) impaired horizontal (wound-healing) and vertical cell migration and invasion (transwell assay) in 2D and BrC (5.0-60 µM) in 3D (ECM Gel®). BrC modulated the expression of genes BIRC5, TNF-α, CASP3, NKX3.1, MMP9, MMP11, CDH1, and ITGAM and downregulated proteins CASP7, BAX, and TNF-α in Western blotting analysis. In conclusion, BrC stimulated cell death and decreased epithelial-mesenchymal transition. Furthermore, DU145 MCTS displayed higher resistance to BrC-induced cell death than 2D cultures, a difference that should be considered in future approaches in prostatic cancer studies.
Assuntos
Antineoplásicos , Neoplasias da Próstata , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Caspase 3/genética , Morte Celular , Linhagem Celular Tumoral , Regulação para Baixo , Flavonoides , Humanos , Masculino , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neoplasias da Próstata/patologia , Microambiente Tumoral , Fator de Necrose Tumoral alfa/genética , Proteína X Associada a bcl-2/genéticaRESUMO
OBJECTIVES: Laryngeal cancer (LC), with a relatively rare diagnosis, is a primary malignancy originating from laryngeal mucosa. This study investigated the mechanisms of microRNA (miR)- 340-5p in LC cell proliferation and invasion. METHODS: The expression patterns of miR-340-5p, long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1), and matrix metallopeptidase 11 (MMP11) in LC cells, tissues, and para-carcinoma tissues, and human bronchial epithelial cells (HBEC) were examined via RT-qPCR. The effects of elevating or silencing miR-340-5p on LC cell proliferation and invasion were examined. The subcellular localization of lncRNA NEAT1 was determined. The binding relations among miR-340-5p, lncRNA NEAT1, and MMP11 were verified. Functional rescue experiments were designed to verify the functions of lncRNA NEAT1 and MMP11 on LC cell proliferation and invasion. Nude-mouse tumor models were established to assess the role of miR-340-5p in LC in vivo. RESULTS: miR-340-5p was under-expressed in LC, and miR-340-5p overexpression repressed LC cell proliferation and invasion. Mechanically, miR-340-5p decreased lncRNA NEAT1 stability via directly binding to lncRNA NEAT1 and thus declined lncRNA NEAT1 expression in LC cells, while lncRNA NEAT1 accelerated MMP11 transcription via binding to heat shock factor 1 (HSF1). Overexpression of lncRNA NEAT1 or MMP11 reversed the repression of miR-340-5p overexpression on LC cell proliferation and invasion. In vivo, miR-340-5p overexpression repressed the tumor growth. CONCLUSION: miR-340-5p overexpression reduced lncRNA NEAT1 stability via binding to lncRNA NEAT1, which declined lncRNA NEAT1 expression and reduced the binding of lncRNA NEAT1 to HSF1 to further inhibit MMP11 transcription, thus repressing LC cell proliferation and invasion.
Assuntos
Neoplasias Laríngeas , MicroRNAs , RNA Longo não Codificante , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Laríngeas/genética , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Camundongos , MicroRNAs/genética , Processos Neoplásicos , RNA Longo não Codificante/genéticaRESUMO
Naked mole-rats (NMRs) (Heterocephalus glaber) are long-lived mammals that possess a natural resistance to cancer and other age-related pathologies, maintaining a healthy life span >30 years. In this study, using immunohistochemical and RNA-sequencing analyses, we compare skin morphology, cellular composition, and global transcriptome signatures between young and aged (aged 3â4 vs. 19â23 years, respectively) NMRs. We show that similar to aging in human skin, aging in NMRs is accompanied by a decrease in epidermal thickness; keratinocyte proliferation; and a decline in the number of Merkel cells, T cells, antigen-presenting cells, and melanocytes. Similar to that in human skin aging, expression levels of dermal collagens are decreased, whereas matrix metalloproteinase 9 and matrix metalloproteinase 11 levels increased in aged versus in young NMR skin. RNA-sequencing analyses reveal that in contrast to human or mouse skin aging, the transcript levels of several longevity-associated (Igfbp3, Igf2bp3, Ing2) and tumor-suppressor (Btg2, Cdkn1a, Cdkn2c, Dnmt3a, Hic1, Socs3, Sfrp1, Sfrp5, Thbs1, Tsc1, Zfp36) genes are increased in aged NMR skin. Overall, these data suggest that specific features in the NMR skin aging transcriptome might contribute to the resistance of NMRs to spontaneous skin carcinogenesis and provide a platform for further investigations of NMRs as a model organism for studying the biology and disease resistance of human skin.
Assuntos
Proteínas Imediatamente Precoces , Envelhecimento da Pele , Animais , Humanos , Camundongos , Genes Supressores de Tumor , Proteínas de Homeodomínio/genética , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Longevidade/genética , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Ratos-Toupeira/genética , Ratos-Toupeira/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , RNA/metabolismo , Envelhecimento da Pele/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Diabetic foot ulceration (DFU) is a devastating complication of diabetes whose pathogenesis remains incompletely understood. Here, we profile 174,962 single cells from the foot, forearm, and peripheral blood mononuclear cells using single-cell RNA sequencing. Our analysis shows enrichment of a unique population of fibroblasts overexpressing MMP1, MMP3, MMP11, HIF1A, CHI3L1, and TNFAIP6 and increased M1 macrophage polarization in the DFU patients with healing wounds. Further, analysis of spatially separated samples from the same patient and spatial transcriptomics reveal preferential localization of these healing associated fibroblasts toward the wound bed as compared to the wound edge or unwounded skin. Spatial transcriptomics also validates our findings of higher abundance of M1 macrophages in healers and M2 macrophages in non-healers. Our analysis provides deep insights into the wound healing microenvironment, identifying cell types that could be critical in promoting DFU healing, and may inform novel therapeutic approaches for DFU treatment.
Assuntos
Diabetes Mellitus/genética , Pé Diabético/genética , Fibroblastos/metabolismo , Macrófagos/metabolismo , Transcriptoma , Cicatrização/genética , Biomarcadores/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Proteína 1 Semelhante à Quitinase-3/genética , Proteína 1 Semelhante à Quitinase-3/metabolismo , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Pé Diabético/metabolismo , Pé Diabético/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fibroblastos/patologia , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Leucócitos/metabolismo , Leucócitos/patologia , Macrófagos/patologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Análise de Célula Única/métodos , Pele/metabolismo , Pele/patologia , Sequenciamento do ExomaRESUMO
Matrix metalloproteinase-11 (MMP-11) promote cancer invasion and metastasis through degrading the extracellular matrix. Protein degradation by MMP-11 in tumor cells may progressively suppress cancer surveillance activities with blocking immune response in breast cancer. The aim of study is to analyze clinicopathological parameters, molecular interactions and anticancer immune response in patients with MMP-11 expression and to provide candidate target drugs. We investigated the clinicopathologic parameters, specific gene sets, tumor antigenicity, and immunologic relevance according to MMP-11 expression in 226 and 776 breast cancer patients from the Hanyang University Guri Hospital (HUGH) cohort and The Cancer Genome Atlas (TCGA) data, respectively. We analyzed pathway networks and in vitro drug response. High MMP-11 expression was associated with worse survival rate in breast cancer from HUGH cohort and TCGA data (all p < 0.05). In analysis of immunologic gene sets, high MMP-11 expression was related to low immune response such as CD8+T cell, CD4+T cell and B cell. In silico cytometry, there was a decrease of cancer testis antigen and low tumor infiltrating lymphocyte in patient with high MMP-11 expression: activated dendritic cell, CD8+T cell, CD4+ memory T cell, and memory B cell. In pathway networks, MMP-11 was linked to the pathways including low immune response, response to growth hormone and catabolic process. We found that pictilisib and AZ960 effectively inhibited the breast cancer cell lines with high MMP-11 expression. Strategies making use of MMP-11-related hub genes could contribute to better clinical management/research for patients with breast cancer.
Assuntos
Neoplasias da Mama/genética , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Metaloproteinase 11 da Matriz/genética , Receptor ErbB-2/genética , Aminopiridinas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indazóis/farmacologia , Células MCF-7 , Pessoa de Meia-Idade , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Análise de Sobrevida , Taxa de Sobrevida , Microambiente TumoralRESUMO
Breast cancer (BC) is one of the most common malignant tumours in women. The matrix metalloproteinase (MMP) enzyme family plays a complex role in the development of BC. There is increasing evidence that MMP11 plays a major role in BC; however, the underlying mechanisms are not clear. The present study confirmed by analysing clinical samples and TCGA data sets, that high expression of MMP11 in clinical samples of BC was strongly associated with a poor prognosis in BC patients. In addition, MTT and colony formation assays indicated that the proliferative capacity of BC was affected when MMP11 expression changed. Furthermore, pathway enrichment analysis was performed and it was revealed that the TGFß signalling pathway was a potential downstream target of MMP11. In the TGFß signalling pathway, MMP11 could significantly regulate the protein expression levels of Smad2 and Smad3 and inhibit the degradation of Smad2 through the ubiquitin proteasome pathway as determined by western blotting. In vivo, it was further verified that MMP11 knockdown could inhibit tumour proliferation and growth. Collectively, the present results demonstrated that MMP11 inhibited the degradation of Smad2 in the TGFß signalling pathway, thereby promoting the development of BC. Thus, MMP11 expression was not only revealed to be an important indicator of BC prognosis but may also be an important therapeutic target for further prevention of BC growth and proliferation. The present study indicated that MMP11targeted therapy may provide new solutions for BC treatment.
Assuntos
Neoplasias da Mama/metabolismo , Metaloproteinase 11 da Matriz/metabolismo , Proteína Smad2/metabolismo , Idoso , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Células MCF-7 , Masculino , Metaloproteinase 11 da Matriz/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Smad2/genéticaRESUMO
BACKGROUND: Chronic hepatitis C (CHC) virus infection is one of major risk factors of hepatocellular carcinoma (HCC) in Egypt, which is a major cause of cancer mortalityin the world. Matrix metalloproteinase-11 (MMP-11) has an important role in tumor migration and metastasis. Therefore, this study aimed to determine relation between MMP-11 gene polymorphisms and risk of HCC development among Egyptian cirrhotic patients. SUBJECTS AND METHODS: Two hundred and sixty patients were included, 140 of them with HCC on top of CHC and 120 patients with post CHC liver cirrhosis (LC) as well as 140 subjects were enrolled in the study as healthy controls. Two single nucleotide polymorphisms (SNPs) rs738791 and rs738792 for MMP-11 gene were done using real-time PCR. RESULTS: Combination of CT and TT allele of rs738791 genotypes was more significantly frequent in HCC compared to LC patients and controls, however, a higher frequency of T allele was found in HCC patients compared to LC and controls. In spite of lake of significant difference between patient groups regarding the rs738792 genotypes, the CC genotype was considered a risk of developing portal vein thrombosis, and was associated with advanced tumor stage, increased tumor size, higher Cancer of the Liver Italian Program [CLIP] score, more advanced Barcelona stage [D] and with child Pugh class [C]. CONCLUSION: Genetic variations in MMP-11 may be implicated in post HCV-HCC development and might be dependable biomarkers for HCC progression.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Predisposição Genética para Doença , Neoplasias Hepáticas/epidemiologia , Metaloproteinase 11 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Biomarcadores Tumorais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Egito/epidemiologia , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Prostate cancer is among the most common malignant tumors worldwide. Matrix metalloproteinase (MMP)-11 is involved in extracellular matrix degradation and remodeling and plays an essential role in cancer development and metastasis. This study investigated the association of MMP-11 polymorphisms with the clinicopathological characteristics and biochemical recurrence of prostate cancer. Five single-nucleotide polymorphisms (SNPs) of the MMP-11 were analyzed in 578 patients with prostate cancer through real-time polymerase chain reaction analysis. A prostate-specific antigen level of >10 ng/mL, Gleason grade groups 4 + 5, advanced tumor stage, lymph node metastasis, invasion, and high-risk D'Amico classification were significantly associated with biochemical recurrence in the patients (p < 0.001). MMP-11 rs131451 "TC + CC" polymorphic variants were associated with advanced clinical stage (T stage; p = 0.007) and high-risk D'Amico classification (p = 0.015) in patients with biochemical recurrence. These findings demonstrate that MMP-11 polymorphisms were not associated with prostate cancer susceptibility; however, the rs131451 polymorphic variant was associated with late-stage tumors and high-risk D'Amico classification in prostate cancer patients with biochemical recurrence. Thus, the MMP-11 SNP rs131451 may contribute to the tumor development in prostate cancer patients with biochemical recurrence.
Assuntos
Metaloproteinase 11 da Matriz , Neoplasias da Próstata , Humanos , Masculino , Metaloproteinase 11 da Matriz/genética , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RecidivaRESUMO
Background: Matrix Metalloproteinases (MMPs) play an indispensable role in the initial alteration and development of PCa. We tried to generate an MMP-related prognostic signature (MMPS) in prostate cancer (PCa). Methods: TCGA-PRAD, MSKCC/GSE21032, GSE116918, GSE70769 cohorts were enrolled to assess the prognostic value of MMPs. The least absolute shrinkage and selection operator (LASSO) Cox regression was employed to generate the MMPS signature. The log-rank test and Kaplan-Meier (K-M) survival curve were applied to show the difference RFS, The receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) was plotted to predict the accuracy of signature. CIBERSORT was conducted to analyze the different immune infiltration in MMPS-H and MMPS-L groups. Potential signaling pathways activated in the MMPS-H groups by Metascape. Results: MMP1, MMP7, MMP11, MMP24 and MMP26 were selected by LASSO regression and established the MMPS predict signature. The MMPS showed the high prognostic value in TCGA-PRAD training cohort (AUC=0.714) and validation cohorts (GSE116918: AUC=0.976, GSE70769: AUC=0.738, MSKCC: AUC=0.793). Pid integrin1 pathway, G2M checkpoint, and response to growth factor signaling pathways were activated in MMPS-H group, patients with the high MMPS risk score and low M2 macrophage showed the worst recurrence-free survival (RFS). Conclusion: MMPs involved and played an essential role in the tumorigenesis and biochemical recurrence in PCa patients. The MMPS signature could accurately predict the recurrence of PCa patients and validated in several cohorts.
Assuntos
Metaloproteinases da Matriz/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Intervalo Livre de Doença , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 11 da Matriz/genética , Metaloproteinase 11 da Matriz/metabolismo , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz Associadas à Membrana/genética , Metaloproteinases da Matriz Associadas à Membrana/metabolismo , Metaloproteinases da Matriz Secretadas/genética , Metaloproteinases da Matriz Secretadas/metabolismo , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Neoplasias da Próstata/metabolismo , Curva ROCRESUMO
OBJECTIVES: Matrix metalloproteinase 11 (MMP-11) was found to be implicated in tumorigenesis in cancers. However, the significance of MMP-11 in pancreatic ductal adenocarcinoma (PDAC) is unclear. METHODS: In the study, we detected malignant biological behaviors of pancreatic cancer after downregulation of MMP-11. Furthermore, we explored the possible mechanism, and the diagnostic value of serum MMP-11 level was analyzed in 116 patients with pathologically confirmed PDAC. In addition, we explored their prognostic value in PDAC. RESULTS: We observed that MMP-11 could be expressed and activated in the cytoplasm of PDAC cells. Immunohistochemistry staining of PDAC tissues showed that MMP-11 was highly expressed in cancerous ductal epithelium instead of cancer stroma. We found that downregulation of MMP-11 inhibited proliferation of PDAC cell lines. The expression levels of cyclin-dependent kinase 4 and cyclin D1 were downregulated after MMP-11 knockdown. As for its clinical value, the serum level of MMP-11 was shown to be a potent promising diagnostic marker for PDAC. CONCLUSIONS: Matrix metalloproteinase 11 may act as a tumor promoter, playing a positive role in PDAC development. Serum MMP-11 also has great potential to be a promising diagnostic marker for PDAC.
Assuntos
Biomarcadores Tumorais/genética , Carcinógenos , Carcinoma Ductal Pancreático/genética , Metaloproteinase 11 da Matriz/genética , Neoplasias Pancreáticas/genética , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/enzimologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaloproteinase 11 da Matriz/sangue , Metaloproteinase 11 da Matriz/metabolismo , Pessoa de Meia-Idade , Pâncreas/enzimologia , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/enzimologia , Prognóstico , Interferência de RNARESUMO
BACKGROUND: Breast cancer is a common type of tumor in women worldwide. MicroRNAs have been identified as regulators in many human cancers. The aim of this study was therefore to investigate the functional role of miR-125b in regulating breast cancer progression. METHODS: We used the StarBase database to investigate the expression of miRNA-125b in breast cancer and adjacent normal tissues. MMP11 3'-UTR construct and luciferase reporter assays was performed for target genes. Cell proliferation was evaluated by CCK-8 and colony formation assay. The migration and invasion were assessed by transwell assay. RESULTS: Luciferase reporter assays showed miRNA-125b directly targeted MMP11. miRNA-125b by transfection with its mimic in breast cancer cells significantly suppressed breast cancer cell proliferation and migration. Western blot revealed that overexpression of miRNA-125b substantially reduced MMP11 protein expression. We used the UALCAN database to investigate the expression of MMP11 in human breast cancer and adjacent normal tissues. In addition, we found that miRNA-125b spoiled MMP11 induced breast cancer cell proliferation and migration promotion effect. CONCLUSIONS: miRNA-125b mimic inhibited proliferation, migration, and invasion of breast cancer cells through targeting MMP11 protein.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Metaloproteinase 11 da Matriz/metabolismo , MicroRNAs/genética , Apoptose , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Movimento Celular , Proliferação de Células , Feminino , Humanos , Metaloproteinase 11 da Matriz/genética , Células Tumorais CultivadasRESUMO
Urothelial cell carcinoma (UCC) is one of the lethal causes of cancer mortality of the genitourinary tract. Carcinogenic epidemiological risk factors exposure and age over 65 years old are associated with UCC risk. Matrix metalloproteinase 11 (MMP11) was suggested as a tumor marker of metastasis and predictor of poor survival in urothelial carcinomas. In this study, we focused on the associations of MMP11 single-nucleotide polymorphisms (SNPs) to UCC susceptibility, clinicopathological characteristics, and prognosis. In this study, real-time polymerase chain reaction was used to analyze five SNPs of MMP11 rs738791, rs2267029, rs738792, rs28382575, and rs131451 in 431 patients with UCC and 650 cancer-free controls. The MMP11 rs28382575 polymorphic "CT" genotype were susceptible to UCC (AOR = 2.045, 95% CI = 1.088 - 3.843; p = 0.026). For MMP11 rs131451, a significant association was found in 166 UCC patients among age ≤ 65 years old who carried MMP11 rs131451 polymorphic "CC" genotype, which is associated with lower risk to develop later tumor T status (T1-T4) (OR = 0.375, 95% CI = 0.159 - 0.887; p = 0.026) compared with the (CT + TT) genotype. Furthermore, patients of UCC with rs738792 polymorphic "CC" genotype were observed to have higher free of relapse (FS) (p = 0.035), disease specific survival rate (p = 0.037), and overall survival rate (p = 0.009) compared with the rs738792 (CT + CC) genotype. In conclusion, our results demonstrated that the MMP11 SNPs are associated with UCC susceptibility, clinical status, and disease survival. The MMP11 polymorphisms may have potential to predict UCC susceptibility and prognosis.
Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Metaloproteinase 11 da Matriz/genética , Recidiva Local de Neoplasia/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias Urológicas/genética , Idoso , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias da Bexiga Urinária/fisiopatologia , Neoplasias Urológicas/fisiopatologiaRESUMO
Tumor-infiltrating immune cells phenotype is associated with tumor progression. However, little is known about the phenotype of the peripheral blood mononuclear cells (PBMC) from breast cancer patients. We investigated MMP1 and MMP11 expression in PBMC from breast cancer patients and we analyzed gene expression changes upon their interaction with cancer cells and cancer-associated fibroblasts (CAF). We measured the impact of PBMC on proinflammatory gene expression in breast cancer cells, normal fibroblast (NF), and CAF and the impact on proliferation and invasiveness capacity of breast cancer cells. Gene expression of MMP1 and MMP11 in PBMC from breast cancer patients (n = 54) and control (n = 28); expression of IL1A, IL6, IL17, IFNß, and NFĸB in breast cancer cell lines (MCF-7 and MDA-MB-231); and, additionally, IL10 and MMP11 in CAF and NF were analyzed by qRT-PCR before and after co-culture. Our results show the existence of a subpopulation of breast cancer patients (25.9%) with very high levels of MMP11 gene expression in PBMC. Also, gene expression of MMP1 and MMP11 increases in PBMC after co-culture with breast cancer cell lines, NF or CAF. PBMC from healthy or breast cancer patients induce an increased proliferation rate on MCF-7 and an increased invasiveness capacity of MDA-MB-231. Finally, we show a differential expression profile of inflammatory genes in NF and CAF when co-cultured with control or breast cancer PBMC. We have observed that MMPs' expression in PBMC is regulated by the microenvironment, while the expression of inflammatory genes in NF or CAF is differentially regulated by PBMC. These findings confirm the importance of the crosstalk between stromal cells and suggest that PBMC would play a role in promoting aggressive tumor behavior.
Assuntos
Neoplasias da Mama/patologia , Fibroblastos Associados a Câncer/patologia , Fibroblastos/patologia , Regulação Enzimológica da Expressão Gênica , Leucócitos Mononucleares/patologia , Metaloproteinase 11 da Matriz/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Estudos de Casos e Controles , Técnicas de Cocultura , Feminino , Fibroblastos/metabolismo , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Leucócitos Mononucleares/metabolismo , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 11 da Matriz/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente TumoralRESUMO
The dysregulation of miR-125a-3p has been observed in multiple tumor types. Nevertheless, the function of miR-125a-3p in papillary thyroid carcinoma (PTC) is yet to be explored. Herein, we find that miR-125a-3p is markedly downregulated in PTC tissues, and its level is inversely related to the histological grade of PTC. Upregulation of miR-125a-3p suppresses the pulmonary metastatic ability as well as the tumor growth of PTC cell in vivo. Consistently, the colony formation ability and other metastasis-related traits of PTC cell are inhibited by miR-125a-3p transfection in vitro. In addition, we identify that matrix metalloprotease 11 (MMP11) is the direct target gene of miR-125a-3p, and that miR-125a-3p inhibits cell viability, migration, and invasiveness of PTC cell by reducing MMP11 expression in vitro. Together, these data testify that the miR-125a-3p/MMP11 axis plays vital roles in the growth and progression of human PTC cells.