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Kinesin Family Member 15 (KIF15) is a plus end-directed microtubule motor, which exerts complex regulations in cancer biology. This study aimed to explore the functional role of KIF15 in leiomyosarcoma (LMS). Bioinformatic analysis was carried out using data from The Cancer Genome Atlas (TCGA)-Sarcoma (SARC). LMS cell lines SK-UT-1 and SK-LMS-1 were used as in vitro cell models. Results showed that LMS patients with high KIF15 expression had significantly worse survival than the low KIF15 expression counterparts. KIF15 knockdown slowed, while KIF15 overexpression increased the proliferation of SK-UT-1 and SK-LMS-1 cells. Co-IP assay confirmed mutual interaction between endogenous KIF15 and DEK (encoded by DEK proto-oncogene). KIF15 knockdown facilitated DEK degradation, while KIF15 overexpression slowed DEK degradation. In ubiquitination assay, a significant increase in DEK polyubiquitylation was observed when KIF15 expression was suppressed. USP15 physically interacted with both DEK and KIF15 in the cells. USP15 knockdown decreased DEK protein stability and canceled KIF15-mediated DEK stabilization. USP15 overexpression enhanced DEK stability, the effect of which was impaired by KIF15 knockdown. USP15 overexpression reduced DEK polyubiquitination. USP15 knockdown increased DEK polyubiquitination and canceled the effect of KIF15 overexpression on reducing DEK polyubiquitination. DEK overexpression enhanced the proliferation of SK-UT-1 and SK-LMS-1 cells. DEK knockdown decreased cell proliferation and canceled the effect of KIF15 overexpression on cell proliferation. In conclusion, this study revealed a novel mechanism that KIF15 enhances LMS cell proliferation via preventing DEK protein from degradation by increasing USP15 mediated deubiquitylation.
Asunto(s)
Proteínas Cromosómicas no Histona/metabolismo , Regulación Neoplásica de la Expresión Génica , Cinesinas/genética , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Proteínas Oncogénicas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Ubiquitinación , Regulación hacia Arriba/genética , Línea Celular Tumoral , Proliferación Celular/genética , Humanos , Cinesinas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Estabilidad Proteica , Proteolisis , Proto-Oncogenes MasRESUMEN
BACKGROUND: A meta-analysis was performed to assess the association between healing rate, avascular necrosis (AVN) of femoral head and two reductions-open reduction internal fixation (ORIF) and closed reduction internal fixation (CRIF) for femoral neck fracture. METHODS: A literature-based search was conducted to identify all relevant studies published before September 10, 2013. The odd ratio (OR) and 95% confidence interval (CI) were used for estimating the effects of the two reduction methods. Data were independently extracted by two investigators who reached a consensus on all of the items. The heterogeneity between studies was examined by χ2-based Q statistic. Egger's regression analysis was used to evaluate publication bias. Statistical analysis was performed by Stata 10.0 software. RESULTS: We examined 14 publications. The results of the present meta-analysis showed that AVN of femoral head were significant associated with the two reductions (CRIF vs. ORIF, OR=1.746, 95% CI 1.159-2.628, p=0.008), while the healing rate were not (CRIF vs. ORIF, OR=0.853, 95% CI 0.573-1.270, p=0.433). CONCLUSION: The present meta-analysis indicated the risk of AVN of femoral head was significant higher after CRIF fixation compared with ORIF, but no association between the healing rate and the two reductions for femoral neck fracture.
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Fracturas del Cuello Femoral/cirugía , Necrosis de la Cabeza Femoral/etiología , Fijación Interna de Fracturas/efectos adversos , Procedimientos de Cirugía Plástica/efectos adversos , Complicaciones Posoperatorias/etiología , Fracturas del Cuello Femoral/diagnóstico , Necrosis de la Cabeza Femoral/diagnóstico , Fijación Interna de Fracturas/tendencias , Humanos , Complicaciones Posoperatorias/diagnóstico , Procedimientos de Cirugía Plástica/tendencias , Resultado del TratamientoRESUMEN
INTRODUCTION: For patients with acetabular osteolytic metastases involving the articular surfaces, current treatments cannot efficiently rebuild the acetabular bone frame structure and strengthen bone defect area mechanics for weight-bearing. The purpose of this study is to show the operational procedure and clinical outcomes of multisite percutaneous bone augmentation (PBA) for the treatment of incidental acetabular osteolytic metastases involving the articular surfaces. METHODS: According to the inclusion and exclusion criteria, 8 patients (4 males and 4 females) were included in this study. Multisite (3 or 4 sites) PBA was successfully performed in all patients. The pain and function evaluation and imaging observation were examined by VAS and Harris hip joint function scores at the different time points (pre-procedure, 7 days, one month, last follow-up in 5-20 months). RESULTS: There were significant differences (p<0.05) in VAS and Harris scores before and after the surgical procedure. Moreover, these two scores had no obvious changes during the follow-up process (7 days after the procedure, one month after the procedure, and the last follow-up) after the procedure. CONCLUSION: The proposed multisite PBA is an effective and safe procedure for the treatment of acetabular osteolytic metastases involving the articular surfaces.
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Background: The dipeptide-alkylated nitrogen-mustard compound is a new kind of nitrogen-mustard derivative with a strong anti-tumor activity, which can be used as a potential anti-osteosarcoma chemotherapy drug. Objective: 2D- and 3D-QSAR (structure-activity relationship quantification) models were established to predict the anti-tumor activity of dipeptide-alkylated nitrogen-mustard compounds. Method: In this study, a linear model was established using a heuristic method (HM) and a non-linear model was established using the gene expression programming (GEP) algorithm, but there were more limitations in the 2D model, so a 3D-QSAR model was introduced and established through the CoMSIA method. Finally, a series of new dipeptide-alkylated nitrogen-mustard compounds were redesigned using the 3D-QSAR model; docking experiments were carried out on several compounds with the highest activity against tumors. Result: The 2D- and 3D-QSAR models obtained in this experiment were satisfactory. A linear model with six descriptors was obtained in this experiment using the HM through CODESSA software, where the descriptor "Min electroph react index for a C atom" has the greatest effect on the compound activity; a reliable non-linear model was obtained using the GEP algorithm model (the best model was generated in the 89th generation cycle, with a correlation coefficient of 0.95 and 0.87 for the training and test set, respectively, and a mean error of 0.02 and 0.06, respectively). Finally, 200 new compounds were designed by combining the contour plots of the CoMSIA model with each other, together with the descriptors in the 2D-QSAR, among which compound I1.10 had a high anti-tumor and docking ability. Conclusion: Through the model established in this study, the factors influencing the anti-tumor activity of dipeptide-alkylated nitrogen-thaliana compounds were revealed, providing direction and guidance for the further design of efficient chemotherapy drugs against osteosarcoma.
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Abnormal loss of components of the extracellular matrix (ECM) including type II collagen and aggrecan caused by proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) is an important pathophysiological characteristic of osteoarthritis (OA). G-protein-coupled bile acid receptor, Gpbar1 (TGR5), is an important member of the bile acid receptor subclass of G Protein-Coupled Receptors (GPCRs). Little information regarding the effects of TGR5 in the pathological development of OA has been reported before. In the current study, we showed that TGR5 is expressed in human primary chondrocytes and human chondrosarcoma SW1353â¯cells. Interestingly, expression of TGR5 was reduced in response to TNF-α treatment in SW1353â¯cells. Our results indicate that activation of TGR5 using its specific agonist INT-777 reduced TNF-α-induced degradation of the articular ECM, including type II collagen and aggrecan, by inhibiting expression of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs- 4 (ADAMTS-4) and ADAMTS-5. We also found that INT-777 treatment inhibited phosphorylation of p38 and activation of the IκB kinase/inhibitory κBα/nuclear factor- κB (IKK/IκBα/NF-κB) signaling pathway. Notably, knockdown of TGR5 abolished the protective effects of INT-777 against ECM degradation, suggesting the involvement of TGR5. Our findings implicate that TGR5 might be considered as a potential therapeutic target for the treatment of OA.
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Agrecanos/metabolismo , Condrocitos/metabolismo , Colágeno Tipo II/metabolismo , Proteolisis , Receptores Acoplados a Proteínas G/metabolismo , Condrocitos/citología , Matriz Extracelular/metabolismo , HumanosRESUMEN
MicroRNAs (miRNAs) are crucial in cancer development. However, the underlying mechanisms of miRNAs in osteosarcoma (OS) remain largely uncharacterized. The present study investigated the role of miR20a in OS cell proliferation. It was determined that miR20a expression is markedly upregulated in OS tissues and cells compared with the matched adjacent normal tissues and hFOB human osteoblast cell lines. Ectopic expression of miR20a promoted the proliferation and anchorageindependent growth of OS cells, whereas inhibition of miR20a reduced this effect. Bioinformatics analysis further revealed early growth response 2 (EGR2), as a potential target of miR20a. Data from luciferase reporter assays showed that miR20a directly binds to the 3'untranslated region (3'UTR) of EGR2 mRNA and represses expression at the transcriptional and translational levels. In functional assays, miR20a promoted OS cell proliferation and the cell cycle, which could be suppressed by an inhibitor of miR20a. In conclusion, the data provide compelling evidence that miR20a functions as an oncomiRNA, which is important in promoting cell proliferation in OS, and its oncogenic effect is mediated primarily through direct suppression of EGR2 expression.