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1.
Biochem Biophys Res Commun ; 716: 150020, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38692011

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with high mortality rates. It has been shown that pirfenidone (PFD) and nintedanib (Ofev) can slow down the decline in lung function of IPF patients, but their efficacy remains suboptimal. Some studies have suggested that the combination of PFD and Ofev may yield promising results. However, there is a lack of research on the combined application of these two medications in the treatment of IPF. A mouse model of bleomycin-induced (BLM) pulmonary fibrosis was established to investigate the impact of combination therapy on pulmonary fibrosis of mice. The findings demonstrated a significant reduction in lung tissue damage in mice treated with the combination therapy. Subsequent transcriptome analysis identified the differential gene secreted phosphoprotein 1 (SPP1), which was found to be associated with macrophages and fibroblasts based on multiple immunofluorescence staining results. Analysis of a phosphorylated protein microarray indicated that SPP1 plays a regulatory role in macrophages and fibroblasts via the AKT pathway. Consequently, the regulation of macrophages and fibroblasts in pulmonary fibrosis by the combination of PFD and Ofev is mediated by SPP1 through the AKT pathway, potentially offering a novel therapeutic option for IPF patients. Further investigation into the targeting of SPP1 for the treatment of pulmonary fibrosis is warranted.


Assuntos
Fibroblastos , Indóis , Macrófagos , Camundongos Endogâmicos C57BL , Osteopontina , Proteínas Proto-Oncogênicas c-akt , Piridonas , Animais , Piridonas/farmacologia , Piridonas/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Osteopontina/metabolismo , Osteopontina/genética , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Antifibróticos/farmacologia , Antifibróticos/uso terapêutico , Masculino , Quimioterapia Combinada , Bleomicina
2.
Hum Vaccin Immunother ; 20(1): 2350101, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38738709

RESUMO

Clinical guidelines have recently advised combination therapy involving immunotherapy (IO) and tyrosine kinase inhibitors (TKI) as the first-line therapy approach for advanced renal cell carcinoma (RCC). Nevertheless, there is currently no available biomarker that can effectively distinguish the progression-free survival (PFS). RNA-sequencing and immunohistochemistry were conducted on our cohort of metastatic RCC patients, namely ZS-MRCC, who received combination therapy consisting of IO and TKI. We further applied RNA-sequencing, immunohistochemistry, and flow cytometry to examine the immune cell infiltration and functionality inside the tumor microenvironment of high-risk localized RCC samples. SPP1 expression was significantly higher in non-responders to IO-TKI therapy. Elevated levels of SPP1 were associated with poor PFS in both the ZS-MRCC cohort (HR = 2.73, p = .018) and validated in the JAVELIN Renal 101 cohort (HR = 1.61, p = .004). By multivariate Cox analysis, SPP1 was identified as a significant independent prognosticator. Furthermore, there existed a negative correlation between elevated levels of SPP1 and the presence of GZMB+CD8+ T cells (Spearman's ρ= -0.48, p < .001). Conversely, SPP1 expression is associated with T cell exhaustion markers. A significant increase in the abundance of Tregs was observed in tumors with high levels of SPP1. Additionally, a machine-learning-based model was constructed to predict the benefit of IO-TKI treatment. High SPP1 is associated with therapeutic resistance and unfavorable PFS in IO-TKI therapy. SPP1 expression have also been observed to be indicative of malfunction and exhaustion in T cells. Increased SPP1 expression has the potential to serve as a potential biomarker for treatment selection of metastatic RCC.


Assuntos
Carcinoma de Células Renais , Imunoterapia , Neoplasias Renais , Osteopontina , Inibidores de Proteínas Quinases , Humanos , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/terapia , Neoplasias Renais/patologia , Masculino , Feminino , Imunoterapia/métodos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Osteopontina/metabolismo , Osteopontina/genética , Idoso , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Prognóstico , Resultado do Tratamento , Adulto , Linfócitos T CD8-Positivos/imunologia , Estudos de Coortes , Terapia Combinada
3.
Cell Stem Cell ; 31(5): 676-693.e10, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38626772

RESUMO

Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by the deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation, and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, which we further characterized by single nucleus RNA sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.


Assuntos
Demência Frontotemporal , Neurônios , Osteopontina , Proteínas tau , Osteopontina/metabolismo , Osteopontina/genética , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Demência Frontotemporal/metabolismo , Humanos , Neurônios/metabolismo , Neurônios/patologia , Animais , Proteínas tau/metabolismo , Camundongos , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Microglia/metabolismo , Microglia/patologia , Mutação/genética
4.
Biochem Pharmacol ; 224: 116208, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38621423

RESUMO

Homeobox B9 (HOXB9) has been shown to play a critical role in several tumors. However, the precise biological mechanisms and functions of HOXB9 in osteosarcoma remain largely unknown. In this study, we found that HOXB9 was increased upon glucose starvation. Elevated HOXB9 suppressed osteosarcoma cell death and supported cell growth and migration under glucose starvation. Further mechanistic studies demonstrated that HOXB9 directly bound to the promoter of secreted phosphoprotein 1 (SPP1) and transcriptionally upregulated SPP1 expression which then led cell death decrease and cell growth increase under glucose deprivation environment. Clinically, HOXB9 was significantly upregulated in osteosarcoma compared with normal tissues and increase of HOXB9 expression was positively associated with the elevation of SPP1 in osteosarcoma. Overall, our study illustrates that HOXB9 contributes to malignancy in osteosarcoma and inhibits cell death through transcriptional upregulating SPP1 under glucose starvation.


Assuntos
Neoplasias Ósseas , Sobrevivência Celular , Glucose , Proteínas de Homeodomínio , Osteopontina , Osteossarcoma , Regulação para Cima , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/genética , Humanos , Glucose/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Linhagem Celular Tumoral , Osteopontina/genética , Osteopontina/metabolismo , Sobrevivência Celular/fisiologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica
5.
PLoS Genet ; 20(4): e1011235, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38648200

RESUMO

Tumor-associated macrophages (TAM) subtypes have been shown to impact cancer prognosis and resistance to immunotherapy. However, there is still a lack of systematic investigation into their molecular characteristics and clinical relevance in different cancer types. Single-cell RNA sequencing data from three different tumor types were used to cluster and type macrophages. Functional analysis and communication of TAM subpopulations were performed by Gene Ontology-Biological Process and CellChat respectively. Differential expression of characteristic genes in subpopulations was calculated using zscore as well as edgeR and Wilcoxon rank sum tests, and subsequently gene enrichment analysis of characteristic genes and anti-PD-1 resistance was performed by the REACTOME database. We revealed the heterogeneity of TAM, and identified eleven subtypes and their impact on prognosis. These subtypes expressed different molecular functions respectively, such as being involved in T cell activation, apoptosis and differentiation, or regulating viral bioprocesses or responses to viruses. The SPP1 pathway was identified as a critical mediator of communication between TAM subpopulations, as well as between TAM and epithelial cells. Macrophages with high expression of SPP1 resulted in poorer survival. By in vitro study, we showed SPP1 mediated the interactions between TAM clusters and between TAM and tumor cells. SPP1 promoted the tumor-promoting ability of TAM, and increased PDL1 expression and stemness of tumor cells. Inhibition of SPP1 attenuated N-cadherin and ß-catenin expression and the activation of AKT and STAT3 pathway in tumor cells. Additionally, we found that several subpopulations could decrease the sensitivity of anti-PD-1 therapy in melanoma. SPP1 signal was a critical pathway of communication between macrophage subtypes. Some specific macrophage subtypes were associated with immunotherapy resistance and prognosis in some cancer types.


Assuntos
Neoplasias , Osteopontina , Macrófagos Associados a Tumor , Humanos , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Prognóstico , Neoplasias/imunologia , Neoplasias/genética , Osteopontina/genética , Osteopontina/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , beta Catenina/genética , beta Catenina/metabolismo , Análise de Célula Única , Transdução de Sinais , Macrófagos/imunologia , Macrófagos/metabolismo , Comunicação Celular/imunologia
6.
Mol Ther ; 32(5): 1425-1444, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38504518

RESUMO

Pathological ocular angiogenesis has long been associated with myeloid cell activation. However, the precise cellular and molecular mechanisms governing the intricate crosstalk between the immune system and vascular changes during ocular neovascularization formation remain elusive. In this study, we demonstrated that the absence of the suppressor of cytokine signaling 3 (SOCS3) in myeloid cells led to a substantial accumulation of microglia and macrophage subsets during the neovascularization process. Our single-cell RNA sequencing data analysis revealed a remarkable increase in the expression of the secreted phosphoprotein 1 (Spp1) gene within these microglia and macrophages, identifying subsets of Spp1-expressing microglia and macrophages during neovascularization formation in angiogenesis mouse models. Notably, the number of Spp1-expressing microglia and macrophages exhibited further elevation during neovascularization in mice lacking myeloid SOCS3. Moreover, our investigation unveiled the Spp1 gene as a direct transcriptional target gene of signal transducer and activator of transcription 3. Importantly, pharmaceutical activation of SOCS3 or blocking of SPP1 resulted in a significant reduction in pathological neovascularization. In conclusion, our study highlights the pivotal role of the SOCS3/STAT3/SPP1 axis in the regulation of pathological retinal angiogenesis.


Assuntos
Modelos Animais de Doenças , Macrófagos , Microglia , Osteopontina , Neovascularização Retiniana , Fator de Transcrição STAT3 , Proteína 3 Supressora da Sinalização de Citocinas , Animais , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Macrófagos/metabolismo , Camundongos , Microglia/metabolismo , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Neovascularização Retiniana/genética , Neovascularização Retiniana/etiologia , Osteopontina/metabolismo , Osteopontina/genética , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Regulação da Expressão Gênica , Transdução de Sinais , Camundongos Knockout , Neovascularização Patológica/metabolismo , Neovascularização Patológica/genética , Angiogênese
7.
Front Immunol ; 15: 1271926, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38426086

RESUMO

Natural components of breast milk, human milk oligosaccharides (HMOs) and osteopontin (OPN) have been shown to have a variety of functional activities and are widely used in infant formulas. However, the preventive and therapeutic effects of both on influenza viruses are not known. In this study, antiviral assays using a human laryngeal carcinoma cell line (HEP-2) showed that 3'-sialyllactose (3'-SL) and OPN had the best antiviral ability with IC50 values of 33.46 µM and 1.65 µM, respectively. 3'-SL (10 µM) and OPN (4 µM) were used in combination to achieve 75% inhibition. Further studies found that the combination of 200 µg/mL of 3'-SL with 500 µg/mL of OPN exerted the best antiviral ability. The reason for this was related to reduced levels of the cytokines TNF-α, IL-6, and iNOS in relation to mRNA expression. Plaque assay and TCID50 assay found the same results and verified synergistic effects. Our research indicates that a combination of 3'-SL and OPN can effectively reduce inflammatory storms and exhibit anti-influenza virus effects through synergistic action.


Assuntos
Influenza Humana , Orthomyxoviridae , Lactente , Feminino , Humanos , Osteopontina/genética , Influenza Humana/tratamento farmacológico , Leite Humano/metabolismo , Oligossacarídeos/farmacologia , Antivirais
8.
Adv Mater ; 36(19): e2311964, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38302097

RESUMO

CRISPR-Cas13 holds substantial promise for tissue repair through its RNA editing capabilities and swift catabolism. However, conventional delivery methods fall short in addressing the heightened inflammatory response orchestrated by macrophages during the acute stages of tendon injury. In this investigation, macrophage-targeting cationic polymers are systematically screened to facilitate the entry of Cas13 ribonucleic-protein complex (Cas13 RNP) into macrophages. Notably, SPP1 (OPN encoding)-producing macrophages are recognized as a profibrotic subtype that emerges during the inflammatory stage. By employing ROS-responsive release mechanisms tailored for macrophage-targeted Cas13 RNP editing systems, the overactivation of SPP1 is curbed in the face of an acute immune microenvironment. Upon encapsulating this composite membrane around the tendon injury site, the macrophage-targeted Cas13 RNP effectively curtails the emergence of injury-induced SPP1-producing macrophages in the acute phase, leading to diminished fibroblast activation and mitigated peritendinous adhesion. Consequently, this study furnishes a swift RNA editing strategy for macrophages in the inflammatory phase triggered by ROS in tendon injury, along with a pioneering macrophage-targeted carrier proficient in delivering Cas13 into macrophages efficiently.


Assuntos
Sistemas CRISPR-Cas , Macrófagos , Traumatismos dos Tendões , Macrófagos/metabolismo , Animais , Camundongos , Traumatismos dos Tendões/terapia , Traumatismos dos Tendões/genética , Imunoterapia , Edição de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células RAW 264.7 , Osteopontina/genética , Osteopontina/metabolismo , Espécies Reativas de Oxigênio/metabolismo
9.
Expert Rev Clin Immunol ; 20(6): 679-693, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38318669

RESUMO

OBJECTIVE: This study aims to explore the relevance of anoikis in idiopathic pulmonary fibrosis (IPF) and identify associated biomarkers and signaling pathways. METHOD: Unsupervised consensus cluster analysis was employed to categorize IPF patients into subtypes. We utilized Weighted Gene Co-Expression Network Analysis (WGCNA) and Protein-Protein Interaction network construction to identify anoikis-related modules and key genes. A prognostic signature was developed using Lasso and multivariate Cox regression analysis. Single-cell sequencing assessed hub gene expression in various cell types, and both cell and animal experiments confirmed IPF-related pathways. RESULTS: We identified two distinct anoikis-associated subtypes with differing prognoses. WGCNA revealed essential hub genes, with SPP1 being prominent in the anoikis-related signature. The anoikis-related signature is effective in determining the prognosis of patients with IPF. Single-cell sequencing highlighted significant differences in SPP1 expression, notably elevated in fibroblasts derived from IPF patients. In vivo and in vitro experiments demonstrated that SPP1 enhances fibrosis in mouse lung fibroblasts by regulating p27 through the PI3K/Akt pathway. CONCLUSION: Our research demonstrates a robust prognostic signature associated with anoikis and highlights SPP1 as a pivotal regulator of the PI3K/AKT signaling pathway in pulmonary fibrosis.


Assuntos
Anoikis , Biomarcadores , Biologia Computacional , Fibrose Pulmonar Idiopática , Osteopontina , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/diagnóstico , Humanos , Animais , Anoikis/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Osteopontina/metabolismo , Osteopontina/genética , Prognóstico , Biomarcadores/metabolismo , Fibroblastos/metabolismo , Modelos Animais de Doenças
10.
Clin Immunol ; 261: 109924, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38310994

RESUMO

Macrophages are the major components of tumour microenvironment, which play critical roles in tumour development. N6-methyladenosine (m6A) also contributes to tumour progression. However, the potential roles of m6A in modulating macrophages in hepatocellular carcinoma (HCC) are poorly understood. Here, we identified ZNNT1 as an HCC-related m6A modification target, which was upregulated and associated with poor prognosis of HCC. METTL3 and METTL16-mediated m6A modification contributed to ZNNT1 upregulation through stabilizing ZNNT1 transcript. ZNNT1 exerted oncogenic roles in HCC. Furthermore, ZNNT1 recruited and induced M2 polarization of macrophages via up-regulating osteopontin (OPN) expression and secretion. M2 Macrophages-recruited by ZNNT1-overexpressed HCC cells secreted S100A9, which further upregulated ZNNT1 expression in HCC cells via AGER/NF-κB signaling. Thus, this study demonstrates that m6A modification activated the ZNNT1/OPN/S100A9 positive feedback loop, which promoted macrophages recruitment and M2 polarization, and enhanced malignant features of HCC cells. m6A modification-triggered ZNNT1/OPN/S100A9 feedback loop represents potential therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamento farmacológico , Osteopontina/genética , Osteopontina/metabolismo , Osteopontina/uso terapêutico , Retroalimentação , Linhagem Celular Tumoral , Macrófagos/metabolismo , Microambiente Tumoral , Metiltransferases/genética , Metiltransferases/metabolismo , Metiltransferases/uso terapêutico
11.
Aging (Albany NY) ; 16(3): 2953-2977, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38329443

RESUMO

OBJECTIVE: The extracellular phosphoprotein, secreted phosphoprotein 1 (SPP1), plays a crucial role in various tumors and regulating the immune system. This study aimed to evaluate its prognostic value and relationship to immune infiltration in lung adenocarcinoma (LUAD). METHODS: In the TCGA and GEO datasets, the information on clinic and transcriptome analysis of SPP1 in non-small-cell lung cancer (NSCLC) was examined accordingly. The association of SPP1 expression with overall survival and clinicopathologic characteristics was investigated by univariate and multivariate analysis. CancerSEA database was utilized to investigate the role of SPP1 at the cellular level by single-cell analysis. Additionally, the CIBERSORT algorithm was utilized to assess the correlation among the immune cells that infiltrated. RESULTS: NSCLC tissues exhibited a notable rise in SPP1 expression compared with that of normal tissues. Furthermore, the overexpression of SPP1 was substantially associated with clinicopathological features and unfavorable survival outcomes in individuals with LUAD, whereas no such correlation was observed in lung squamous cell carcinoma. Immune cells that infiltrate tumors and their corresponding genes were associated with SPP1 expression levels in LUAD. CONCLUSIONS: SPP1 is a reliable indicator for assessing LUAD immune infiltration status and prognosis. With this approach, SPP1 can help earlier LUAD diagnosis and act as a possible immunotherapy target.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Osteopontina/genética , Prognóstico , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/genética
12.
Theriogenology ; 217: 159-168, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38280277

RESUMO

Endometrial epidermal growth factor (EGF) shows a cyclic change with two peaks on days 2-4 and days 13-14 of the estrous cycle. In repeat breeder cows, loss of the peaks has been associated with reduced fertility. By infusing seminal plasma (SP) and osteopontin (OPN) derived from SP and milk into the vagina, their EGF profile and fertility are restored. However, SP is difficult to obtain, and both SP and OPN can transmit infectious diseases. While OPN can be sourced from recombinant protein without this risk, recombinant bovine OPN (rOPN) expressed in Escherichia coli should be examined for its effects on the EGF profile, since it does not undergo posttranslational modification, which is important for its biological activity. In study 1, PBS, SP (0.5 mL), and rOPN (0.3 mg) were infused into the vagina at estrus (day 0) in 74, 37, and 105 repeat breeder Holstein cows, respectively, with an altered EGF profile. The endometrial EGF concentrations were measured on day 3. Some cows (n = 58, 20, and 83, respectively) were inseminated immediately before the infusion and then diagnosed for pregnancy between days 30 and 35. The normalization rate of the EGF profile and conception rate in the rOPN group (58.1 % and 47.0 %, respectively) were not significantly different from those in the SP group (62.2 % and 45.0 %, respectively) but higher than those in PBS group (29.7 % and 28.1 %, respectively) (P < 0.05). In study 2, repeat breeder cows with an altered EGF profile were infused with PBS (n = 18) and rOPN (n = 17), while fertile controls with a normal EGF profile (n = 18) were infused with PBS. Two or three embryos were transferred into cows on day 7 and then recovered on day 14. Embryo recovery rates of the rOPN and fertile groups were comparable (58.7 % vs. 58.3 %) but higher than that of the PBS group (58.7 % vs. 32.0 %) (P < 0.05). The embryo recovery rate of cows with normalized EGF profile was higher than that of cows with unnormalized EGF profile (64.4 % vs. 16.7 %) (P < 0.05). The embryo sizes of cows in the rOPN and fertile groups were comparable but larger than those in the PBS group (P < 0.05). However, the embryo size was not correlated to the corresponding endometrial EGF concentrations. In conclusion, rOPN without posttranslational modifications normalized the EGF profile in repeat breeder cows. Improved fertility by normalization of the EGF profile could be attributed partly to the increased embryo viability up to day 14.


Assuntos
Fator de Crescimento Epidérmico , Escherichia coli , Gravidez , Feminino , Bovinos , Animais , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/farmacologia , Fator de Crescimento Epidérmico/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Osteopontina/genética , Fertilidade , Progesterona
13.
J Biomol Struct Dyn ; 42(3): 1336-1351, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37096999

RESUMO

NIH reported 128 different types of cancer of which lung cancer is the leading cause of mortality. Globally, it is estimated that on average one in every seventeen hospitalized patients was deceased. There are plenty of studies that have been reported on lung cancer draggability and therapeutics, but yet a protein that plays a central specific to cure the disease remains unclear. So, this study is designed to identify the possible therapeutic targets and biomarkers that can be used for the potential treatment of lung cancers. In order to identify differentially expressed genes, 39 microarray datasets of lung cancer patients were obtained from various demographic regions of the GEO database available at NCBI. After annotating statistically, 6229 up-regulated genes and 10324 down-regulated genes were found. Out of 17 up-regulated genes and significant genes, we selected SPP1 (osteopontin) through virtual screening studies. We found functional interactions with the other cancer-associated genes such as VEGF, FGA, JUN, EGFR, and TGFB1. For the virtual screening studies,198 biological compounds were retrieved from the ACNPD database and docked with SPP1 protein (PDBID: 3DSF). In the results, two highly potential compounds secoisolariciresinol diglucoside (-12.9 kcal/mol), and Hesperidin (-12.0 kcal/mol) showed the highest binding affinity. The stability of the complex was accessed by 100 ns simulation in an SPC water model. From the functional insights obtained through these computational studies, we report that SPP1 could be a potential biomarker and successive therapeutic protein target for lung cancer treatment.


Assuntos
Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/genética , Pulmão/metabolismo , Perfilação da Expressão Gênica , Expressão Gênica , Osteopontina/genética , Osteopontina/metabolismo
14.
Lung ; 202(1): 25-39, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38060060

RESUMO

Osteopontin (OPN) is a multifunctional phosphorylated protein that is involved in physiological and pathological events. Emerging evidence suggests that OPN also plays a critical role in the pathogenesis of respiratory diseases. OPN can be produced and secreted by various cell types in lungs and overexpression of OPN has been found in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pulmonary hypertension (PH), pulmonary fibrosis diseases, lung cancer, lung infection, chronic obstructive pulmonary disease (COPD), and asthma. OPN exerts diverse effects on the inflammatory response, immune cell activation, fibrosis and tissue remodeling, and tumorigenesis of these respiratory diseases, and genetic and pharmacological moudulation of OPN exerts therapeutic effects in the treatment of respiratory diseases. In this review, we summarize the recent evidence of multifaceted roles and underlying mechanisms of OPN in these respiratory diseases, and targeting OPN appears to be a potential therapeutic intervention for these diseases.


Assuntos
Hipertensão Pulmonar , Fibrose Pulmonar , Síndrome do Desconforto Respiratório , Humanos , Osteopontina/genética , Osteopontina/metabolismo , Pulmão/patologia , Fibrose Pulmonar/patologia , Hipertensão Pulmonar/etiologia , Síndrome do Desconforto Respiratório/metabolismo , Fibrose
15.
Clin Transl Sci ; 17(1): e13694, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38058256

RESUMO

Osteopontin (OPN) is a secreted integrin-binding protein that plays a role in inflammation, cellular viability, cell adhesion and migration, cancer development, and diabetes through different mechanisms. The splice variants of OPN can play essential roles in cancer development, progression, and metastasis formation; however, limited data are available about the role of OPN isoforms in human malignant melanoma. Our goal was to define the gene expression patterns of five OPN variants (OPN4, OPN5, OPNa, OPNb, and OPNc), integrin, and CD44 receptor genes in primary and metastatic melanoma-originated cell lines (n = 19), and to explore the association of the expression patterns with clinicopathological parameters. We evaluated the invasive property of the cell lines and investigated the potential association between the invasion and gene expression of OPN isoforms. We found a significant rise in the expression of OPNc in the invasive cell lines compared to the noninvasive cells and detected significantly higher expression of the OPN splice variants in melanoma cell lines originating from more advanced stages tumors than cell lines originating from early-stage melanomas. The correlation analysis revealed that all five OPN variants positively correlated with ITGB3 and ITGA9, whereas OPN5 positively correlated with ITGB1, ITGAV, ITGA6, and CD44. OPN can activate extracellular signal-regulated kinase signaling through binding to α9ß1 integrin, promoting melanoma tumor cell migration. It is possible that such associations between OPN splice variants and integrin receptors may play a role in melanoma progression. In conclusion, our findings suggest that high expression of OPNc correlates with the invasive behavior of melanoma cells.


Assuntos
Melanoma , Humanos , Osteopontina/genética , Osteopontina/metabolismo , Linhagem Celular Tumoral , Isoformas de Proteínas/genética , Integrinas , Movimento Celular
16.
Cardiovasc Res ; 120(4): 417-432, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-37976180

RESUMO

AIMS: Abdominal aortic aneurysm (AAA) is a highly lethal disease with progressive dilatation of the abdominal aorta accompanied by degradation and remodelling of the vessel wall due to chronic inflammation. Platelets play an important role in cardiovascular diseases, but their role in AAA is poorly understood. METHODS AND RESULTS: The present study revealed that platelets play a crucial role in promoting AAA through modulation of inflammation and degradation of the extracellular matrix (ECM). They are responsible for the up-regulation of SPP1 (osteopontin, OPN) gene expression in macrophages and aortic tissue, which triggers inflammation and remodelling and also platelet adhesion and migration into the abdominal aortic wall and the intraluminal thrombus (ILT). Further, enhanced platelet activation and pro-coagulant activity result in elevated gene expression of various cytokines, Mmp9 and Col1a1 in macrophages and Il-6 and Mmp9 in fibroblasts. Enhanced platelet activation and pro-coagulant activity were also detected in AAA patients. Further, we detected platelets and OPN in the vessel wall and in the ILT of patients who underwent open repair of AAA. Platelet depletion in experimental murine AAA reduced inflammation and ECM remodelling, with reduced elastin fragmentation and aortic diameter expansion. Of note, OPN co-localized with platelets, suggesting a potential role of OPN for the recruitment of platelets into the ILT and the aortic wall. CONCLUSION: In conclusion, our data strongly support the potential relevance of anti-platelet therapy to reduce AAA progression and rupture in AAA patients.


Assuntos
Aneurisma da Aorta Abdominal , Metaloproteinase 9 da Matriz , Humanos , Animais , Camundongos , Metaloproteinase 9 da Matriz/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Aneurisma da Aorta Abdominal/metabolismo , Aorta Abdominal/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Fibroblastos/metabolismo
17.
Naunyn Schmiedebergs Arch Pharmacol ; 397(2): 1025-1035, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37566308

RESUMO

Primary hepatic carcinoma (PHC) is a leading threat to cancer patients with few effective treatment strategies. OPN is found to be an oncogene in hepatocellular carcinoma (HCC) with potential as a treating target for PHC. Fenofibrate is a lipid-lowering drug with potential anti-tumor properties, which is claimed with suppressive effects on OPN expression. Our study proposes to explore the molecular mechanism of fenofibrate in inhibiting HCC. OPN was found extremely upregulated in 6 HCC cell lines, especially Hep3B cells. Hep3B and Huh7 cells were treated with 75 and 100 µM fenofibrate, while OPN-overexpressed Hep3B cells were treated with 100 µM fenofibrate. Decreased clone number, elevated apoptotic rate, reduced number of migrated cells, and shortened migration distance were observed in fenofibrate-treated Hep3B and Huh7 cells, which were markedly abolished by the overexpression of OPN. Furthermore, the facilitating effect against apoptosis and the inhibitory effect against migration of fenofibrate in Hep3B cells were abolished by 740 Y-P, an agonist of PI3K. Hep3B xenograft model was established, followed by treated with 100 mg/kg and 200 mg/kg fenofibrate, while OPN-overexpressed Hep3B xenograft was treated with 200 mg/kg fenofibrate. The tumor growth was repressed by fenofibrate, which was notably abolished by OPN overexpression. Furthermore, the inhibitory effect of fenofibrate on the PI3K/AKT/Twist pathway in Hep3B cells and Hep3B xenograft model was abrogated by OPN overexpression. Collectively, fenofibrate suppressed progression of hepatoma downregulating OPN through inhibiting the PI3K/AKT/Twist pathway.


Assuntos
Carcinoma Hepatocelular , Fenofibrato , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Osteopontina/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células
18.
Hepatol Int ; 18(1): 73-90, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38159218

RESUMO

PURPOSE: Cytokeratin 19-positive cancer stem cells (CK19 + CSCs) and their tumor-associated macrophages (TAMs) have not been fully explored yet in the hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Single-cell RNA sequencing was performed on the viable cells obtained from 11 treatment-naïve HBV-associated HCC patients, including 8 CK19 + patients, to elucidate their transcriptomic landscape, CK19 + CSC heterogeneity, and immune microenvironment. Two in-house primary HCC cohorts (96 cases-related HBV and 89 cases with recurrence), TCGA external cohort, and in vitro and in vivo experiments were used to validate the results. RESULTS: A total of 64,581 single cells derived from the human HCC and adjacent normal tissues were sequenced, and 11 cell types were identified. The result showed that CK19 + CSCs were phenotypically and transcriptionally heterogeneous, co-expressed multiple hepatics CSC markers, and were positively correlated with worse prognosis. Moreover, the SPP1 + TAMs (TAM_SPP1) with strong M2-like features and worse prognosis were specifically enriched in the CK19 + HCC and promoted tumor invasion and metastasis by activating angiogenesis. Importantly, matrix metalloproteinase 9 (MMP9) derived from TAM_SPP1, as the hub gene of CK19 + HCC, was activated by the VEGFA signal. CONCLUSIONS: This study revealed the heterogeneity and stemness characteristics of CK19 + CSCs and specific immunosuppressive TAM_SPP1 in CK19 + HCC. The VEGFA signal can activate TAM_SPP1-derived MMP9 to promote the invasion and metastasis of CK19 + HCC tumors. This might provide novel insights into the clinical treatment of HCC patients.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Vírus da Hepatite B/genética , Metaloproteinase 9 da Matriz/genética , Queratina-19/genética , Queratina-19/metabolismo , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia , Células-Tronco Neoplásicas , Análise de Sequência de RNA , Microambiente Tumoral , Osteopontina/genética , Osteopontina/metabolismo
19.
Cells ; 12(23)2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-38067149

RESUMO

Osteopontin (OPN)-CD44 signaling plays an important role in promoting tumor progression and metastasis. In cancer, OPN and CD44 overexpression is a marker of aggressive disease and poor prognosis, and correlates with therapy resistance. In this study, we aimed to evaluate the association of single nucleotide polymorphisms (SNPs) in the OPN and CD44 genes with clinical outcomes in 307 non-small cell lung cancer (NSCLC) patients treated with radiotherapy or chemoradiotherapy. The potential impact of the variants on plasma OPN levels was also investigated. Multivariate analysis showed that OPN rs11730582 CC carriers had a significantly increased risk of death (p = 0.029), while the CD44 rs187116 A allele correlated with a reduced risk of locoregional recurrence (p = 0.016) in the curative treatment subset. The rs11730582/rs187116 combination was associated with an elevated risk of metastasis in these patients (p = 0.016). Furthermore, the OPN rs1126772 G variant alone (p = 0.018) and in combination with rs11730582 CC (p = 7 × 10-5) was associated with poor overall survival (OS) in the squamous cell carcinoma subgroup. The rs11730582 CC, rs187116 GG, and rs1126772 G, as well as their respective combinations, were independent risk factors for unfavorable treatment outcomes. The impact of rs11730582-rs1126772 haplotypes on OS was also observed. These data suggest that OPN and CD44 germline variants may predict treatment effects in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia , Receptores de Hialuronatos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Recidiva Local de Neoplasia , Osteopontina/genética , Resultado do Tratamento , Radioterapia
20.
J Recept Signal Transduct Res ; 43(4): 102-108, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38082480

RESUMO

Autophagy is a dynamic intracellular process of protein degradation, which is mostly triggered by nutrient deprivation. This process initiates with the formation of autophagosomes, which they capture cytosolic material that is then degraded upon fusion with the lysosome. Several factors have been found to be associated with autophagy modulation, of which extracellular matrix (ECM) components has attracted the attention of recent studies. Osteopontin (OPN) is an important extracellular matrix component that has been detected in a wide range of tumor cells, and is involved in cancer cell invasion and metastasis. Recently, a number of studies have focused on the relationship of OPN with autophagy, by delineating the intracellular signaling pathways that connect OPN to the autophagy process. We will summarize signaling pathways and cell surface receptors, through which OPN regulates the process of autophagy.


Assuntos
Neoplasias , Osteopontina , Humanos , Osteopontina/genética , Osteopontina/metabolismo , Transdução de Sinais/genética , Neoplasias/genética , Neoplasias/metabolismo , Autofagia/genética
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