RESUMO
(1) Background: Periostin (Pn) is a secreted protein found in the extracellular matrix, and it plays a variety of roles in the human body. Physiologically, Pn has a variety of functions, including bone formation and wound healing. However, it has been implicated in the pathogenesis of various malignant tumors and chronic inflammatory diseases. Pn has alternative splicing variants (ASVs), and our previous research revealed that aberrant ASVs contribute to the pathogenesis of breast cancer and heart failure. However, the difference in expression pattern between physiologically expressed Pn-ASVs and those expressed during pathogenesis is not clear. (2) Methods and results: We examined normal and breast cancer tissues, focusing on the Pn-ASVs expression pattern to assess the significance of pathologically expressed Pn-ASVs as potential diagnostic and therapeutic targets. We found that most physiologically expressed Pn isoforms lacked exon 17 and 21. Next, we used human breast cancer and normal adjacent tissue (NAT) to investigate the expression pattern of Pn-ASVs under pathological conditions. Pn-ASVs with exon 21 were significantly increased in tumor tissues compared with NAT. In situ hybridization identified the synthesis of Pn-ASVs with exon 21 in peri-tumoral stromal cells. Additionally, the in vivo bio-distribution of 89Zr-labeled Pn antibody against exon 21 (Pn-21Ab) in mice bearing breast cancer demonstrated selective and specific accumulation in tumors, while Pn-21Ab significantly suppressed tumor growth in the mouse breast cancer model. (3) Conclusions: Together, these data indicate that Pn-ASVs might have potential for use as diagnostic and therapeutic targets for breast cancer.
Assuntos
Processamento Alternativo , Neoplasias da Mama , Moléculas de Adesão Celular , Humanos , Processamento Alternativo/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Animais , Camundongos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Regulação Neoplásica da Expressão Gênica , Éxons/genética , PeriostinaRESUMO
The role of periostin (POSTN) in remodeling the microenvironment surrounding solid tumors and its effect on the tumor cells in non-small-cell lung carcinoma (NSCLC) have not yet been fully understood. The aim of this study was to determine the relationship between POSTN expression (in tumor cells [NSCLC cells] and the tumor stroma) and pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and microvascular density (MVD) in NSCLC. In addition, these associations were analyzed in individual histological subtypes of NSCLC (SCC, AC, and LCC) and their correlations with clinicopathological factors and prognosis were examined. Immunohistochemistry using tissue microarrays (TMAs) was used to assess the expression of POSTN (in tumor cells and cancer-associated fibroblasts [CAFs]) and the pro-angiogenic factors. A significant positive correlation was found between the expression of POSTN (in cancer cells/CAFs) and the expression of the analyzed pro-angiogenic factors (CD31, CD34, CD105, and VEGF-A) and MVD in the entire population of patients with NSCLC and individual histological subtypes (AC, SCC). In addition, this study found that POSTN expression (in tumor cells/CAFs) increased with tumor size (pT), histopathological grade (G), and lymph-node involvement (pN). In addition, a high expression of POSTN (in tumor cells and CAFs) was associated with shorter survival among patients with NSCLC. In conclusion, a high expression of POSTN (in cancer cells and CAFs) may be crucial for angiogenesis and NSCLC progression and can constitute an independent prognostic factor for NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Moléculas de Adesão Celular , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Moléculas de Adesão Celular/metabolismo , Feminino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Idoso , Neovascularização Patológica/metabolismo , Prognóstico , Indutores da Angiogênese/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , PeriostinaRESUMO
BACKGROUND: Periostin (POSTN) is a type of matrix protein that functions by binding to other matrix proteins, cell surface receptors, or other molecules, such as cytokines and proteases. POSTN has four major splicing variants (PN1-4), which are primarily expressed in fibroblasts and cancer. We have reported that we should inhibit pathological POSTN (PN1-3), but not physiological POSTN (PN4). In particular, pathological POSTN with exon 17 is present in both stroma and cancer, but it is unclear whether the stroma or cancer pathological POSTN should be suppressed. METHODS AND RESULTS: We transplanted 4T1 cells (breast cancer) secreting POSTN with exon 17 into 17KO mice lacking POSTN exon 17 to suppress stromal POSTN with exon 17. The results show that 17KO mice had smaller primary tumors and fewer metastases. Furthermore, to suppress cancer POSTN with exon 17, 4T1 cells transfected with POSTN exon 17 skipping oligo or control oligo were transplanted from the tail vein into the lungs. The results show that POSTN exon 17 skipping oligo significantly suppressed lung metastasis. CONCLUSIONS: These findings suggest that it is important to suppress POSTN exon 17 in both stroma and cancer. Antibody targeting POSTN exon 17 may be a therapeutic candidate for breast cancer.
Assuntos
Moléculas de Adesão Celular , Éxons , Células Estromais , Animais , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Éxons/genética , Camundongos , Feminino , Linhagem Celular Tumoral , Células Estromais/metabolismo , Células Estromais/patologia , Humanos , Processamento Alternativo/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Camundongos Knockout , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos BALB C , PeriostinaRESUMO
Tongue squamous cell carcinoma (TSCC) occurs frequently in the oral cavity, and because of its high proliferative and metastatic potential, it is necessary to develop a novel treatment for it. We have reported the importance of the inhibition of the periostin (POSTN) pathological splicing variant, including exon 21 (PN1-2), in various malignancies, but its influence is unclear in tongue cancer. In this study, we investigated the potential of POSTN exon 21-specific neutralizing antibody (PN21-Ab) as a novel treatment for TSCC. Human PN2 was transfected into the human TSCC (HSC-3) and cultured under stress, and PN2 was found to increase cell viability. PN2 induced chemotherapy resistance in HSC-3 via the phosphorylation of the cell survival signal Akt. In tissues from human TSCC and primary tumors of an HSC-3 xenograft model, PN1-2 was expressed in the tumor stroma, mainly from fibroblasts. The intensity of PN1-2 mRNA expression was positively correlated with malignancy. In the HSC-3 xenograft model, CDDP and PN21-Ab promoted CDPP's inhibition of tumor growth. These results suggest that POSTN exon 21 may be a biomarker for tongue cancer and that PN21-Ab may be a novel treatment for chemotherapy-resistant tongue cancer. The treatment points towards important innovations for TSCC, but many more studies are needed to extrapolate the results.
Assuntos
Moléculas de Adesão Celular , Resistencia a Medicamentos Antineoplásicos , Éxons , Neoplasias da Língua , Humanos , Neoplasias da Língua/patologia , Neoplasias da Língua/genética , Neoplasias da Língua/tratamento farmacológico , Neoplasias da Língua/metabolismo , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Animais , Éxons/genética , Linhagem Celular Tumoral , Camundongos , Masculino , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Processamento Alternativo/genética , Processamento Alternativo/efeitos dos fármacos , Pessoa de Meia-Idade , Camundongos Endogâmicos BALB C , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , PeriostinaRESUMO
Anterior cruciate ligament (ACL) injuries pose a significant challenge due to their limited healing potential, often resulting in premature arthritis. The factors and mechanisms contributing to this inadequate healing process remain elusive. During the acute phase of injury, ACL tissues express elevated periostin levels that decline over time. The functional significance of periostin in ligament biology remains understudied. In this study, we investigated the functional and mechanistic implications of periostin deficiency in ACL biology, utilizing ligament fibroblasts derived from patients and a murine model of ACL rupture. Our investigations unveiled that periostin knockdown compromised fibroblast growth characteristics, hindered the egress of progenitor cells from explants, and arrested cell-cycle progression, resulting in the accumulation of cells in the G0/G1 phase and moderate apoptosis. Concurrently, a significant reduction in the expression of cell-cycle and matrix-related genes was observed. Moreover, periostin deficiency triggered apoptosis through STAT3Y705/p38MAPK signaling and induced cellular senescence through increased production of reactive oxygen species (ROS). Mechanistically, inhibition of ROS production mitigated cell senescence in these cells. Notably, in vivo data revealed that ACL in Postn-/- mice exhibited a higher tearing frequency than wild-type mice under equivalent loading conditions. Furthermore, injured ACL with silenced periostin expression, achieved through nanoparticle-siRNA complex delivery, displayed an elevated propensity for apoptosis and senescence compared to intact ACL in C57BL/6 mice. Together, our findings underscore the pivotal role of periostin in ACL health, injury, and potential for healing.
Assuntos
Lesões do Ligamento Cruzado Anterior , Ligamento Cruzado Anterior , Senescência Celular , Fibroblastos , Periostina , Espécies Reativas de Oxigênio , Animais , Feminino , Humanos , Masculino , Camundongos , Ligamento Cruzado Anterior/metabolismo , Lesões do Ligamento Cruzado Anterior/metabolismo , Lesões do Ligamento Cruzado Anterior/patologia , Apoptose , Células Cultivadas , Senescência Celular/fisiologia , Fibroblastos/metabolismo , Camundongos Endogâmicos C57BL , Periostina/genética , Periostina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that plays a key role in drug metabolism. Recently, PXR was found to attenuate the development of liver cancer by suppressing epithelial-mesenchymal transition (EMT) in liver cancer cells in a mouse model of two-stage chemical carcinogenesis. To elucidate the role of PXR in the EMT of liver cancer cells, we focused on its role in hepatic stellate cells (HSCs), which are components of the tumor microenvironment in hepatocellular carcinoma (HCC). Human HSC-derived LX-2 cells stably expressed destabilization domain (DD)-fused human PXR (hPXR-LX2 cells). Human HCC-derived HepG2 cells were transfected with the EMT marker VIM promoter-regulated reporter plasmid and co-cultured with hPXR-LX2 cells or treated with hPXR-LX2-derived conditioned medium (CM). Co-culture or CM treatment increased reporter activity in HepG2 cells. This induction was attenuated upon PXR activation in hPXR-LX2 cells by treatment with the DD-stabilizing chemical Shield-1 and the human PXR ligand rifampicin. PXR activation in hPXR-LX2 cells exhibited inhibition of TGF-ß1-induced transdifferentiation, supported by observations of morphological changes and protein or mRNA levels of the transdifferentiation markers COL1A1 and FN1. PXR activation in hPXR-LX2 cells also attenuated the mRNA levels of the key transdifferentiation factor, POSTN. Treatment of hPXR-LX2 cells with recombinant POSTN restored the PXR-mediated suppression of transdifferentiation. Reporter assays with the POSTN promoter showed that PXR inhibited the NF-κB-mediated transcription of POSTN. Consequently, PXR activation in HSCs is expected to inhibit transdifferentiation by down-regulating POSTN expression, thereby suppressing EMT of liver cancer cells.
Assuntos
Moléculas de Adesão Celular , Transdiferenciação Celular , Regulação para Baixo , Células Estreladas do Fígado , Receptor de Pregnano X , Humanos , Receptor de Pregnano X/metabolismo , Receptor de Pregnano X/genética , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Transdiferenciação Celular/efeitos dos fármacos , Células Hep G2 , Regulação para Baixo/efeitos dos fármacos , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , PeriostinaRESUMO
Management of skin injuries imposes a substantial financial burden on patients and hospitals, leading to diminished quality of life. Periostin (rhOSF), an extracellular matrix component, regulates cell function, including a proliferative healing phase, representing a key protein to promote wound healing. Despite its proven efficacy in vitro, there is a lack of scaffolds that facilitate the in situ delivery of rhOSF. In addition, there is a need for a scaffold to not only support cell growth, but also to resist the mechanical forces involved in wound healing. In this work, we synthesized rhOSF-loaded mesoporous nanoparticles (MSNs) and incorporated them into a cell-laden gelatin methacryloyl (GelMA) ink that was bioprinted into melt electrowritten poly(ε-caprolactone) (PCL) microfibrous (MF-PCL) meshes to develop mechanically competent constructs. Diffraction light scattering (DLS) analysis showed a narrow nanoparticle size distribution with an average size of 82.7 ± 13.2 nm. The rhOSF-loaded hydrogels showed a steady and controlled release of rhOSF over 16 days at a daily dose of â¼40 ng/mL. Compared with blank MSNs, the incorporation of rhOSF markedly augmented cell proliferation, underscoring its contribution to cellular performance. Our findings suggest a promising approach to address challenges such as prolonged healing, offering a potential solution for developing robust, biocompatible, and cell-laden grafts for burn wound healing applications.
Assuntos
Gelatina , Metacrilatos , Nanopartículas , Periostina , Poliésteres , Alicerces Teciduais , Cicatrização , Humanos , Bioimpressão/métodos , Proliferação de Células/efeitos dos fármacos , Gelatina/química , Hidrogéis/química , Metacrilatos/química , Nanopartículas/química , Periostina/administração & dosagem , Poliésteres/química , Porosidade , Alicerces Teciduais/química , Cicatrização/efeitos dos fármacosRESUMO
OBJECTIVES: This study aimed to investigate the temporal and spatial changes in the expression of periostin during periodontal inflammation in mice. METHODS: A periodontitis model was constructed using silk thread ligation. Mice were randomly divided into five groups including control group, 4-day ligation group, 7-day ligation group, 14-day ligation group, and self-healing group (thread removal for 14 days after 14-day ligation). Micro-CT and histological staining were performed to characterize the dynamic changes in the mouse periodontal tissue in each group. RNAscope and immunohistochemical staining were used to analyze the pattern of changes in periostin at various stages of periodontitis. The cell experiment was divided into three groups: control group, lipopolysaccharide (LPS) stimulation group (treated with LPS for 12 h), and LPS stimulation removal group (treated with LPS for 3 h followed by incubation with medium for 9 h). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of periostin, transforming growth factor-ß1 (TGF-ß1), and matrix metalloproteinase 2 (MMP2). RESULTS: Significant alveolar bone resorption was observed 7 days after ligation. With increasing duration of ligation, the damage to the mouse periodontal tissue was aggravated, which manifested as increased osteoclasts, widening of the periodontal membrane space, and decreased alveolar bone height. Some degree of periodontal tissue repair was observed in the self-healing group. Periostin expression decreased at 4 and 7 days compared with the control group and increased at 14 days compared with 4 and 7 days. A significant recovery was found in the self-healing group. The qRT-PCR results showed that the expression of periostin and TGF-ß1 in the LPS stimulation group decreased compared with that in the control group but significantly recovered in the LPS removal group. CONCLUSIONS: Periostin expression in the PDL of mice showed a downward and upward trend with inflammation progression. The significant recovery of periostin expression after removing inflammatory stimuli may be related to TGF-ß1, which is crucial to maintain the integrity of the PDL.
Assuntos
Perda do Osso Alveolar , Moléculas de Adesão Celular , Modelos Animais de Doenças , Lipopolissacarídeos , Periodontite , Fator de Crescimento Transformador beta1 , Animais , Moléculas de Adesão Celular/metabolismo , Camundongos , Periodontite/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Perda do Osso Alveolar/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Microtomografia por Raio-X , PeriostinaRESUMO
INTRODUCTION: Periostin is a matricellular protein. Elevated serum concentrations of periostin have been reported in patients with various cardiovascular diseases, including heart failure. Patients with end-stage renal disease have a substantially increased risk for cardiovascular diseases. However, there is a lack of clinical studies to clarify the prognostic significance of systemic periostin on all-cause mortality in patients with end-stage renal disease on hemodialysis. METHODS: 313 stable end-stage renal disease patients were recruited and followed for 5 years concerning all-cause mortality. At baseline, we collected blood samples and clinical data. Serum periostin concentrations were measured using a certified ELISA. RESULTS: The optimal cut-off value for serum periostin regarding all-cause mortality, calculated through receiver operating characteristic analysis, was 777.5 pmol/L. Kaplan-Meier survival analysis using this cut-off value demonstrated that higher periostin concentrations are linked to higher all-cause mortality (log-rank test: p = 0.002). Subgroup analysis revealed that serum periostin concentrations only affected all-cause mortality in male but not in female patients (p = 0.002 in male patients and p = 0.474 in female patients). Multivariate Cox regression analyses, adjusted for confounding factors, likewise showed that elevated serum periostin concentrations were positively associated with all-cause mortality in male (p = 0.028) but not in female patients on hemodialysis (p = 0.313). CONCLUSION: Baseline serum periostin is an independent risk factor for all-cause mortality in male patients with chronic renal disease on hemodialysis.
Assuntos
Moléculas de Adesão Celular , Falência Renal Crônica , Diálise Renal , Humanos , Moléculas de Adesão Celular/sangue , Feminino , Falência Renal Crônica/terapia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Idoso , Fatores Sexuais , Prognóstico , Causas de Morte/tendências , Biomarcadores/sangue , Fatores de Risco , Curva ROC , Estimativa de Kaplan-Meier , PeriostinaRESUMO
OBJECTIVE: There is growing evidence suggesting a relationship between periostin levels, inflammation, and ovarian dysfunction. In this prospective case-control study, we aimed to investigate serum periostin levels and their relationship with metabolic parameters in patients with polycystic ovary syndrome. METHODS: We conducted a prospective case-control study involving 45 polycystic ovary syndrome patients and 45 control subjects, matched in a 1:1 ratio. Serum samples collected from both study and control groups were analyzed using enzyme-linked immunosorbent assay. RESULTS: The demographic characteristics were similar between the polycystic ovary syndrome and control groups (p>0.05). Periostin levels were significantly higher in patients with polycystic ovary syndrome compared with the control group (4.67±2.46 vs. 2.60±1.41 ng/mL, respectively; p=0.000). CONCLUSION: Our study revealed a significant elevation in periostin levels among polycystic ovary syndrome patients compared with controls. These findings suggest that periostin could serve as a potential marker for assessing disease severity in polycystic ovary syndrome patients.
Assuntos
Biomarcadores , Moléculas de Adesão Celular , Ensaio de Imunoadsorção Enzimática , Síndrome do Ovário Policístico , Humanos , Síndrome do Ovário Policístico/sangue , Feminino , Moléculas de Adesão Celular/sangue , Estudos de Casos e Controles , Estudos Prospectivos , Adulto , Biomarcadores/sangue , Adulto Jovem , Índice de Gravidade de Doença , Índice de Massa Corporal , PeriostinaRESUMO
Periostin is a matricellular protein known to be alternatively spliced to produce ten isoforms with a molecular weight of 78-91 kDa. Within the extracellular matrix, periostin attaches to cell surfaces to induce signaling via integrin-binding and actively participates in fibrillogenesis, orchestrating the arrangement of collagen in the extracellular environment. In atopic diseases such as atopic dermatitis (AD) and asthma, periostin is known to participate in driving the disease-causing type 2 inflammation. The periostin isoforms expressed in these diseases and the implication of the alternative splicing events are unknown. Here, we present two universal assays to map the expression of periostin isoforms at the mRNA (RT-qPCR) and protein (PRM-based mass spectrometry) levels. We use these assays to study the splicing profile of periostin in AD lesions as well as in in vitro models of AD and asthma. In these conditions, periostin displayed overexpression with isoforms 3 and 5 standing out as highly overexpressed. Notably, isoforms 9 and 10 exhibited a divergent pattern relative to the remaining isoforms. Isoforms 9 and 10 are often overlooked in periostin research and this paper presents the first evidence of their expression at the protein level. This underlines the necessity to include isoforms 9 and 10 in future research addressing periostin splice isoforms. The assays presented in this paper hold the potential to improve our insight into the splicing profile of periostin in tissues and diseases of interest. The application of these assays to AD lesions and in vitro models demonstrated their potential for identifying isoforms of particular significance, warranting a further in-depth investigation.
Assuntos
Processamento Alternativo , Asma , Moléculas de Adesão Celular , Dermatite Atópica , Isoformas de Proteínas , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Dermatite Atópica/metabolismo , Dermatite Atópica/genética , Asma/metabolismo , Asma/genética , Humanos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Espectrometria de Massas/métodos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , PeriostinaRESUMO
Renal fibrosis is the most common pathway in progressive kidney diseases. The unilateral ureteral obstruction (UUO) model is used to induce progressive renal fibrosis. We evaluated the effects of irisin on renal interstitial fibrosis in UUO mice. The GSE121190, GSE36496, GSE42303, and GSE96101 datasets were downloaded from the Gene Expression Omnibus (GEO) database. In total, 656 differentially expressed genes (DEGs) were identified in normal and UUO mouse renal samples. Periostin and matrix metalloproteinase-2 (MMP-2) were selected to evaluate the effect of irisin on renal fibrosis in UUO mice. In UUO mice, irisin ameliorated renal function, decreased the expression of periostin and MMP-2, and attenuated epithelial-mesenchymal transition and extracellular matrix deposition in renal tissues. In HK-2 cells, irisin treatment markedly attenuated TGF-ß1-induced expression of periostin and MMP-2. Irisin treatment also inhibited TGF-ß1-induced epithelial-mesenchymal transition, extracellular matrix formation, and inflammatory responses. These protective effects of irisin were abolished by the overexpression of periostin and MMP-2. In summary, irisin treatment can improve UUO-induced renal interstitial fibrosis through the TGF-ß1/periostin/MMP-2 signaling pathway, suggesting that irisin may be used for the treatment of renal interstitial fibrosis.
Assuntos
Moléculas de Adesão Celular , Transição Epitelial-Mesenquimal , Fibronectinas , Fibrose , Nefropatias , Metaloproteinase 2 da Matriz , Transdução de Sinais , Fator de Crescimento Transformador beta1 , Obstrução Ureteral , Animais , Obstrução Ureteral/complicações , Obstrução Ureteral/patologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/tratamento farmacológico , Fibronectinas/metabolismo , Camundongos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Masculino , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/etiologia , Nefropatias/tratamento farmacológico , Rim/patologia , Rim/metabolismo , Rim/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Linhagem Celular , Modelos Animais de Doenças , PeriostinaRESUMO
Colorectal cancer (CRC) is the third most common malignancy cause of cancer-related mortality worldwide. Epithelial-mesenchymal transition (EMT) promotes cancer metastasis and a tumour-based Glasgow EMT score was associated with adverse clinical features and poor prognosis. In this study, the impact of using the established five tumour-based EMT markers consisting of E-cadherin (E-cad), ß-catenin (ß-cat), Snail, Zeb-1, and Fascin in combination with the stromal periostin (PN) on the prediction of CRC patients' prognosis were invesigated. Formalin-fixed paraffin-embedded tissues of 202 CRC patients were studies the expressions of E-cad, ß-cat, Snail, Zeb-1, Fascin, and PN by immunohistochemistry. Individually, cytoplasmic Fascin (Fc), cytoplasmic Snail (Sc), nuclear Snail (Sn), stromal Snail (Ss), and stromal PN (Ps) were significantly associated with reduced survival. A combination of Ps with Fc, Fs, and Sn was observed in 2 patterns including combined Fc, Fs, and Ps (FcFsPs) and Fc, Sn, and Ps (FcSnPs). These combinations enhanced the prognostic power compared to individual EMT markers and were independent prognostic markers. As the previously established scoring method required five markers and stringent criteria, its clinical use might be limited. Therefore, using these novel combined prognostic markers, either FcFsPs or FcSnPs, may be useful in predicting CRC patient outcomes.
Assuntos
Biomarcadores Tumorais , Proteínas de Transporte , Moléculas de Adesão Celular , Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Proteínas dos Microfilamentos , Fatores de Transcrição da Família Snail , Humanos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Fatores de Transcrição da Família Snail/metabolismo , Moléculas de Adesão Celular/metabolismo , Prognóstico , Feminino , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte/metabolismo , Proteínas dos Microfilamentos/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Adulto , Caderinas/metabolismo , Fatores de Transcrição/metabolismo , beta Catenina/metabolismo , Idoso de 80 Anos ou mais , PeriostinaRESUMO
Collagen crosslinking, mediated by lysyl oxidase, is an adaptive mechanism of the cardiac repair process initiated by cardiac fibroblasts postmyocardial injury. However, excessive crosslinking leads to cardiac wall stiffening, which impairs the contractile properties of the left ventricle and leads to heart failure. In this study, we investigated the role of periostin, a matricellular protein, in the regulation of lysyl oxidase in cardiac fibroblasts in response to angiotensin II and TGFß1. Our results indicated that periostin silencing abolished the angiotensin II and TGFß1-mediated upregulation of lysyl oxidase. Furthermore, the attenuation of periostin expression resulted in a notable reduction in the activity of lysyl oxidase. Downstream of periostin, ERK1/2 MAPK signaling was found to be activated, which in turn transcriptionally upregulates the serum response factor to facilitate the enhanced expression of lysyl oxidase. The periostin-lysyl oxidase association was also positively correlated in an in vivo rat model of myocardial infarction. The expression of periostin and lysyl oxidase was upregulated in the collagen-rich fibrotic scar tissue of the left ventricle. Remarkably, echocardiography data showed a reduction in the left ventricular wall movement, ejection fraction, and fractional shortening, indicative of enhanced stiffening of the cardiac wall. These findings shed light on the mechanistic role of periostin in the collagen crosslinking initiated by activated cardiac fibroblasts. Our findings signify periostin as a possible therapeutic target to reduce excessive collagen crosslinking that contributes to the structural remodeling associated with heart failure.
Assuntos
Moléculas de Adesão Celular , Fibroblastos , Proteína-Lisina 6-Oxidase , Ratos Sprague-Dawley , Animais , Proteína-Lisina 6-Oxidase/metabolismo , Fibroblastos/metabolismo , Ratos , Moléculas de Adesão Celular/metabolismo , Masculino , Sistema de Sinalização das MAP Quinases , Miocárdio/metabolismo , Miocárdio/citologia , Angiotensina II/farmacologia , Angiotensina II/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Células Cultivadas , Modelos Animais de Doenças , PeriostinaRESUMO
BACKGROUND: The incremental biological changes in the synovial microenvironment of the shoulder in acute and chronic instability that may contribute to joint degeneration are poorly understood. Proteomic analysis of synovial fluid in patients with shoulder instability may improve our understanding of proteins that are shed into shoulder synovial fluid after an injury. HYPOTHESIS: Injury-specific factors such as the direction of instability and the severity of glenoid and humeral bone loss are associated with the proteome of synovial fluid in patients with shoulder instability. STUDY DESIGN: Descriptive laboratory study. METHODS: Synovial fluid lavage samples were compared between patients with anterior (n = 12) and posterior (n = 8) instability and those without instability (n = 5). Synovial proteins were identified with liquid chromatography-tandem mass spectrometry. Orthogonal validation of protein targets found to be significant on tandem mass spectrometry was performed in a separate set of prospective patients with Western blotting. Data were processed and analyzed, and P values were adjusted with the Benjamini-Hochberg method for multiple comparisons. RESULTS: A total of 25 patients were included. Tandem mass spectrometry identified 720 protein groups in synovial fluid of patients with shoulder instability. There were 4 synovial proteins that were significantly expressed in patients with anterior instability relative to posterior instability: periostin (POSTN) (adjusted P value = .03; log fold change [logFc] = 4.7), transforming growth factor beta-induced protein ig-h3 (adjusted P value = .05; logFc = 1.7), collagen type VI alpha-3 chain (adjusted P value = .04; logFc = 2.6), and coagulation factor V (adjusted P value = .04; logFc = -3.3). Among these targets, POSTN showed a moderate correlation with the Hill-Sachs lesion size (r = 0.7). Prospective validation with Western blotting confirmed a significantly higher level of POSTN in synovial fluid of patients with anterior instability (P = .00025; logFc = 5.1). CONCLUSION: Proteomic analysis enriched our understanding of proteins that were secreted into shoulder synovial fluid of patients with shoulder instability. The identification of POSTN, a proinflammatory catabolic protein involved with tissue remodeling and repair, as a significant target in anterior shoulder instability is a novel finding. Therefore, further study is warranted to determine the role that POSTN may play in the progression of bone loss and posttraumatic osteoarthritis. CLINICAL RELEVANCE: Proteomic analysis of synovial fluid in patients with shoulder instability improved our understanding of this abnormality after an injury.
Assuntos
Biomarcadores , Moléculas de Adesão Celular , Instabilidade Articular , Proteômica , Líquido Sinovial , Humanos , Líquido Sinovial/metabolismo , Líquido Sinovial/química , Instabilidade Articular/metabolismo , Feminino , Biomarcadores/metabolismo , Biomarcadores/análise , Masculino , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/análise , Adulto , Adulto Jovem , Articulação do Ombro/metabolismo , Adolescente , Espectrometria de Massas em Tandem , PeriostinaRESUMO
Background: Periostin (POSTN) is a critical extracellular matrix protein in various tumor microenvironments. However, the function of POSTN in thyroid cancer progression remains largely unknown. Methods: Postn and Rag1 knock-out mice and orthotopic mouse models were used to determine the role of POSTN on papillary thyroid tumor progression. Immunofluorescence, cell co-culture, fluorescence in situ hybridization, chromatin immunoprecipitation assay, recombinant protein and inhibitor treatment were performed to explore the underlying mechanisms of POSTN-promoted papillary thyroid tumor growth. Results: POSTN is up-regulated in papillary thyroid tumors and negatively correlates with the overall survival of patients with thyroid cancer. Cancer-associated fibroblast (CAF)-derived POSTN promotes papillary thyroid tumor growth in vivo and in vitro. POSTN deficiency in CAFs significantly impairs CAF-promoted papillary thyroid tumor growth. POSTN promotes papillary thyroid tumor cell proliferation and IL-4 expression through integrin-FAK-STAT3 signaling. In turn, tumor cell-derived IL-4 induces the activation of CAFs and stimulates POSTN expression by activating STAT6. We reveal the crucial role of CAF-derived POSTN and tumor cell-derived IL-4 in driving the development of papillary thyroid tumors through the POSTN-integrin-FAK-STAT3-IL-4 pathway in tumor cells and IL-4-STAT6-POSTN signaling in CAFs. Conclusion: Our findings underscore the significance of POSTN and IL-4 as critical molecular mediators in the dynamic interplay between CAFs and tumor cells, ultimately supporting the growth of papillary thyroid tumors.
Assuntos
Fibroblastos Associados a Câncer , Proliferação de Células , Camundongos Knockout , Periostina , Fator de Transcrição STAT3 , Transdução de Sinais , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Animais , Humanos , Camundongos , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Quinase 1 de Adesão Focal/metabolismo , Integrinas/metabolismo , Interleucina-4/metabolismo , Periostina/metabolismo , Fator de Transcrição STAT3/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Microambiente TumoralAssuntos
Asma , Produtos Biológicos , Moléculas de Adesão Celular , Escarro , Humanos , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Moléculas de Adesão Celular/metabolismo , Antiasmáticos/uso terapêutico , Resultado do Tratamento , Índice de Gravidade de Doença , Masculino , Feminino , PeriostinaRESUMO
Tendon-derived cells exhibit phenotypic changes and gradually lose their proliferative capacity during serial passages in vitro. This study aimed to characterize the changes in the growth and stem cell characteristics of tendon-derived cells over a long-term culture. Mouse flexor digitorum profundus tendon-derived cells were obtained by enzymatic digestion and seeded at an initial density of 5,000/cm2. Cells were characterized by morphology, growth, senescence staining, trilineage differentiation assays, real-time polymerase chain reaction, immunocytochemistry, flow cytometry, and RNA sequencing analysis. Tendon-derived cells underwent a proliferative stage in the first three passages, followed by a gradual senescence. However, a novel cell population expressing periostin (Postn+) emerged during the long-term culture from passages 5-8, which possessed a high rate of proliferation without significant senescence over successive passages. Compared to early passage cells, Postn+ cells exhibited enhanced osteogenic differentiation potential and attenuated chondrogenic differentiation potential, decreased expression of SSEA-1, Oct3/4, tenomodulin, scleraxis, CD90.2, CD73, CD105, Sca-1, and CD44, and increased expression of collagen III and CD34. RNA-sequencing analysis of Postn+ and early passage cells identified 908 differentially expressed genes, with extracellular matrix-receptor interaction and focal adhesion as the top pathways, and integrins as hub genes. This study highlights the dynamics of tendon-derived cells during serial passages. We identify a Postn+ cell population during long-term culture in late passages, with high proliferative ability and prominent osteogenic differentiation potential. Further investigations are needed to elucidate the origin and potential applications of Postn+ tendon-derived cells.
Assuntos
Moléculas de Adesão Celular , Diferenciação Celular , Proliferação de Células , Tendões , Animais , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/genética , Tendões/citologia , Tendões/metabolismo , Camundongos , Células Cultivadas , Osteogênese/genética , Técnicas de Cultura de Células/métodos , Condrogênese/genética , Células-Tronco/metabolismo , Células-Tronco/citologia , PeriostinaRESUMO
OBJECTIVE: Cytokines are involved in the inflammatory/anti-inflammatory balance and have been shown to play an important role in the course of COVID-19. This study aimed to evaluate the relationship of periostin, transforming growth factor-beta (TGF-ß), interleukin-18 (IL-18), and matrix metalloproteinase 7 (MMP-7) levels with clinical course and mortality in patients with early COVID-19 pneumonia. PATIENTS AND METHODS: A total of 150 hospitalized patients were diagnosed with COVID-19 between June and October 2021, and a control group of 30 healthy individuals were included in our study. The COVID-19 patients were divided into those who developed macrophage activation syndrome (MAS) in Group 1 and those who did not in Group 2. Serum periostin, MMP-7, TGF-ß, and IL-18 levels were measured from blood samples obtained at admission using enzyme-linked immunosorbent assay (ELISA). RESULTS: Periostin, MMP-7, and IL-18 levels were significantly higher in COVID-19 patients compared to the control group (p<0.001 for all). Periostin and MMP-7 levels were also significantly higher in Group 1 than in Group 2 (p<0.001 for both). Periostin, MMP-7, IL-18, and TGF-ß levels were significantly higher in non-surviving patients compared to survivors (p=0.04, p<0.001, p<0.001, and p<0.001, respectively). In the receiver operating characteristic (ROC) curve analysis, MMP-7 was found to have high sensitivity (90%) at a predictive value of 2.66 ng/mL. CONCLUSIONS: It is still not possible to predict which patients with early COVID-19 pneumonia will go on to develop MAS despite receiving standard treatment. The results of our study suggest that elevation of periostin and MMP-7 levels in the early period may predict the development of macrophage activation syndrome.
Assuntos
COVID-19 , Síndrome de Ativação Macrofágica , Humanos , Fator de Crescimento Transformador beta , Interleucina-18 , Metaloproteinase 7 da Matriz , Periostina , Prognóstico , Progressão da DoençaRESUMO
Uterine leiomyomas, also known as fibroids or myomas, occur in an estimated 70-80% of reproductive aged women. Many experience debilitating symptoms including pelvic pain, abnormal uterine bleeding (AUB), dyspareunia, dysmenorrhea, and infertility. Current treatment options are limited in preserving fertility, with many opting for sterilizing hysterectomy as a form of treatment. Currently, surgical interventions include hysterectomy, myomectomy, and uterine artery embolization in addition to endometrial ablation to control AUB. Non-surgical hormonal interventions, including GnRH agonists, are connotated with negative side effects and are unacceptable for women desiring fertility. Periostin, a regulatory extra cellular matrix (ECM) protein, has been found to be expressed in various gynecological diseases including leiomyomas. We previously determined that periostin over-expression in immortalized myometrial cells led to the development of a leiomyoma-like cellular phenotype. Periostin is induced by TGF-ß, signals through the PI3K/AKT pathway, induces collagen production, and mediates wound repair and fibrosis, all of which are implicated in leiomyoma pathology. Periostin has been linked to other gynecological diseases including ovarian cancer and endometriosis and is being investigated as pharmacological target for treating ovarian cancer, post-surgical scarring, and numerous other fibrotic conditions. In this review, we provide discussion linking pathological inflammation and wound repair, with a TGF-ß-periostin-collagen signaling in the pathogenesis of leiomyomas, and ultimately the potential of periostin as a druggable target to treat leiomyomas.