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1.
Genet Mol Biol ; 46(3): e20230002, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37791813

RESUMO

KDELR2 has been reported as a promotive factor for the genesis and progression of several malignancies. However, it is uncertain how it affects bladder urothelial carcinoma (BLCA). Using data extracted from online databases, an enhanced expression of KDELR2 in BLCA tissues was verified. Overexpression of KDELR2 was correlated with advanced clinicopathologic characteristics and unfavourable prognosis of BLCA. Receiver operating characteristic analysis highlighted the potential diagnostic value of KDELR2. Univariate and multivariate logistic regression analyses further revealed the predictive effect of KDELR2 for the prognosis of BLCA. KDELR2 was primarily enriched in biological functions related to organization of the extracellular matrix. TIMER, ssGSEA and GEPIA analyses suggested that KDELR2 expression is positively related to the infiltration of macrophages, Th2 cells and neutrophils. Finally, knocking-down of KDELR2 in T24 cells resulted in reduced proliferation, migration and macrophages recruitment. These results suggest that KDELR2 overexpression is an indicator for poor prognosis of BLCA and it has the potential to be employed as an immunotherapy target for BLCA.

2.
Mol Cancer Ther ; 19(2): 650-660, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31694887

RESUMO

Bone metastasis is a severe complication associated with various carcinomas. It causes debilitating pain and pathologic fractures and dramatically impairs patients' quality of life. Drugs aimed at osteoclast formation significantly reduce the incidence of skeletal complications and are currently the standard treatment for patients with bone metastases. Here, we reported that serum- and glucocorticoid-inducible kinase 1 (SGK1) plays a pivotal role in the formation and function of osteoclasts by regulating the Ca2+ release-activated Ca2+ channel Orai1. We showed that SGK1 inhibition represses osteoclastogenesis in vitro and prevents bone loss in vivo Furthermore, we validated the effect of SGK1 on bone metastasis by using an intracardiac injection model in mice. Inhibition of SGK1 resulted in a significant reduction in bone metastasis. Subsequently, the Oncomine and the OncoLnc database were employed to verify the differential expression and the association with clinical outcome of SGK1 gene in patients with breast cancer. Our data mechanistically demonstrated the regulation of the SGK1 in the process of osteoclastogenesis and revealed SGK1 as a valuable target for curing bone metastasis diseases.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Proteínas Imediatamente Precoces/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Benzoatos/farmacologia , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/genética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Proteínas Imediatamente Precoces/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteína ORAI1/metabolismo , Osteoclastos/enzimologia , Osteoclastos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Ligante RANK/antagonistas & inibidores , Ligante RANK/metabolismo , Transdução de Sinais , Transfecção
3.
J Cancer ; 10(16): 3706-3716, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31333788

RESUMO

Osteosarcoma (OS) is the most common primary bone tumor, whose poor prognosis is mainly due to lung metastasis. The aim of this study is to build a practical and valid diagnostic test that can predict the risk of OS metastasis and progression. We performed weighted gene co-expression network analysis (WGCNA) on GSE21257 from the Gene Expression Omnibus (GEO) database, which contains microarray data of biopsies from OS patients. In these modules, the highest association was found between the blue module and metastasis stage (r = -0.52) by Pearson's correlation analysis. Based on Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression, we derived eight clinically significant genes and constructed an eight-gene signature for metastasis status. It showed great efficacy to distinguish metastasis from non-metastasis (AUC = 0.886) and the results were validated in The Cancer Genome Atlas (TCGA) database. Functional enrichment analysis of hub genes showed that their biological processes focused on immune-related pathways, suggesting the important roles of immune cells, immune pathways and the tumor microenvironment in metastasis development. In conclusion, we discovered an efficient gene signature with great efficacy to distinguish metastasis status, which may help improve early diagnosis and treatment, enhancing the clinical outcomes of OS patients. Besides we created an effective protocol to seek for several hub genes in high-throughput data by combining WGCNA and LASSO Cox regression.

4.
Sci Rep ; 7(1): 2328, 2017 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-28539667

RESUMO

The loosening of implants is an important clinical issue, particularly for patients with osteoporosis. In these patients, an implant should preferably both promote osteoblast differentiation and repress osteoclastic resorption. In the present study, we fabricated coatings containing TiO2 nanotubes (NTs) incorporated with strontium (Sr) on titanium (Ti) surfaces through hydrothermal treatment. The amount of loaded Sr was controlled by hydrothermally treating the samples in a Sr(OH)2 solution for 1 and 3 h (samples NT-Sr1h and NT-Sr3h, respectively) and found that both types of NT-Sr samples inhibited osteoclast differentiation by reducing the expression of osteoclast marker genes. Additionally, this inhibitory effect was mainly attributed to suppression of RANKL-induced activation of nuclear factor-κB (NF-κB). Moreover, NT-Sr also inhibited the Akt and nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) signalling pathways. Interestingly, we also found that NT-Sr promoted RANKL-induced extracellular signal-regulated kinase (ERK) phosphorylation. Using ovariectomised rats as a model, we observed that NT-Sr prevented bone loss in vivo. In conclusion, our findings demonstrate that NT-Sr might effectively inhibit osteoclast differentiation by repressing the NF-κB and Akt/NFATc1 pathways and by negatively regulating the ERK pathway in vitro and in vivo.


Assuntos
Reabsorção Óssea/prevenção & controle , Nanotubos/química , Osteogênese/efeitos dos fármacos , Osteoporose/prevenção & controle , Animais , Reabsorção Óssea/genética , Reabsorção Óssea/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Fatores de Transcrição NFATC/genética , Osteoclastos/efeitos dos fármacos , Osteoporose/genética , Osteoporose/fisiopatologia , Osteoporose/cirurgia , Ligante RANK/genética , Ratos , Estrôncio/química , Estrôncio/uso terapêutico , Titânio/química , Titânio/uso terapêutico
5.
Oncotarget ; 8(3): 3781-3797, 2017 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-28052015

RESUMO

Intervertebral disc (IVD) degeneration is considered a common cause of low back pain. In the degenerating IVD, the production of pro-inflammatory cytokines, including IL-1 and TNF-α, progressively increases, contributing to the degenerative process. Epoxyeicosatrienoic acids (EETs), synthesized from arachidonic acid by cytochrome P450 enzymes, act as autocrine and paracrine effectors in regulating inflammation, cardiovascular functions, and angiogenesis. EETs were shown to be especially potent promoters of tissue regeneration. Considering their anti-inflammatory and anti-catabolic potential, we investigated whether EETs can influence IVD degeneration. We found that 14,15-EET protected rat nucleus pulposus (NP) cells against death induced by treatment with H2O2and TNF-α in vitro. At the molecular level, 14,15-EET significantly inhibited the NF-κB pathway, which plays essential roles in the degeneration and survival of NP cells. As a result, 14,15-EET efficiently prevented the matrix remodeling response of NP cells to TNF-α. Using a needle-punctured rat tail model, the influence of 14,15-EET on IVD degeneration in vivo was evaluated using radiographs, magnetic resonance images (MRI), and histological analysis. We observed that 14,15-EET prevented IVD degeneration. Our findings demonstrated that 14,15-EET can enhance the survival of NP cells and inhibit IVD degeneration. The EET pathway may be a novel therapeutic target against IVD degeneration.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Degeneração do Disco Intervertebral/prevenção & controle , Núcleo Pulposo/citologia , Ácido 8,11,14-Eicosatrienoico/administração & dosagem , Ácido 8,11,14-Eicosatrienoico/farmacologia , Animais , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Peróxido de Hidrogênio/efeitos adversos , Degeneração do Disco Intervertebral/diagnóstico por imagem , Masculino , NF-kappa B/metabolismo , Núcleo Pulposo/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos adversos
6.
Sci Rep ; 5: 16835, 2015 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-26568463

RESUMO

FOXO transcription factors especially FOXO1 have profound roles in bone development and remodeling. The regulation of cells of the osteoblast lineage by FOXOs is suggested to be stage-specific or context dependent. Intriguingly, recent studies on the role played by FOXOs in osteoclastogenesis reached different conclusion. Bartell et al. showed that FOXOs restrained osteoclastogenesis and bone resorption partially by upregulation of the H2O2-inactivating enzyme catalase. Wang et al. demonstrated that FOXO1 activated osteoclast formation. In the present study, we confirmed the results of Bartell et al. that FOXO1 expression was reduced upon stimulation of RANKL; FOXO1 inhibition promoted and FOXO1 activation repressed, osteoclast differentiation and activity; the inhibitory effect of FOXO1 on osteoclastogenesis was partially mediated by ROS since treatment with ROS scavengers cancelled the effect of FOXO1 inhibition on osteoclastogenesis. We further investigated the mechanisms responsible for repressed osteoclastogenesis by FOXO1. We found that FOXO1 inhibition modulated MAPKs, NF-κB and AP-1. Finally, we proved that the inhibitory effect of FOXO1 on osteoclast formation was partially mediated by MYC suppression by showing that MYC repression almost totally abrogated the effect of FOXO1 inhibition on osteoclastogenesis. To conclude, our study confirmed FOXO1 as a cell-autonomous inhibitor of osteoclastogenesis.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/agonistas , Fatores de Transcrição Forkhead/antagonistas & inibidores , Sequestradores de Radicais Livres/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Quinolonas/farmacologia , Ligante RANK/farmacologia , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição AP-1/genética , Regulação para Cima/efeitos dos fármacos
7.
J Nanosci Nanotechnol ; 15(6): 4136-42, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26369022

RESUMO

Implants that can inhibit osteoclastogenesis and enhance osteogenesis are desirable for osteoporosis patients. In this study, titania nanotube (Ti-NT) materials, having nanotube diameters of 30, 80, and 120 nm, were produced separately by anodization at 10, 40, and 60 V, respectively. The introduction of Ti-NTs to titanium substrates significantly reduced the formation and activity of osteoclasts on samples. With the enlargement of the nanotube diameter, the osteoclasts number, tartrate-resistant acid phosphatase staining and activity, and related gene expressions of osteoclasts were further reduced. Osteogenic ability was enhanced by increasing the nanotube diameter. Thus, larger-diameter nanotube implants, such as NT60, were better able to inhibit bone absorption and enhance bone formation to prevent implant loss and failure, especially for osteoporosis patients.


Assuntos
Nanotubos/química , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Titânio/química , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/citologia , Osteoclastos/metabolismo , Tamanho da Partícula , Propriedades de Superfície , Titânio/farmacologia
8.
Cell Signal ; 27(5): 969-77, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25683916

RESUMO

DNA methylation is essential for maintenance of stable repression of gene transcription during differentiation and tumorigenesis. Demethylating reagents including decitabine could release the repression, leading to perturbed transcription program. Recently others and we showed that, in B cell lymphomas, decitabine repressed B cell specific gene transcription and activated NF-κB signaling, causing decreased expression of translocated oncogenes including MYC and attenuated tumor cell proliferation. During osteoclastogenesis, changes in DNA methylation occurred in numerous genes, implicating important roles for DNA methylation in osteoclastogenesis. In the present study, we found that decitabine inhibited osteoclastogenesis. The inhibitory effect could be at least partially attributed to reduced expression of multiple osteoclast specific genes including RANK by decitabine. Moreover, decitabine inhibited activity of NF-κB, AP-1 and extracellular signal-regulated kinase (ERK), but not PI3K/Akt pathway. In vivo, using ovariectomized mouse as a model, we observed that decitabine reduced the osteoclast activity and bone loss. In conclusion, our findings demonstrated that decitabine was an inhibitor of osteoclastogenesis by repression of osteoclast specific transcription program including the RANK, NF-κB and AP-1 pathways. DNA methylation might be indispensable for osteoclastogenesis. The use of decitabine could represent a novel strategy in treatment of diseases associated with increased osteoclast activity.


Assuntos
Azacitidina/análogos & derivados , Diferenciação Celular/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Ligante RANK/antagonistas & inibidores , Animais , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Reabsorção Óssea/prevenção & controle , Linhagem Celular , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/antagonistas & inibidores , Decitabina , Feminino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteoclastos/patologia , Ligante RANK/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo
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