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1.
Front Bioeng Biotechnol ; 11: 1247165, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37811370

RESUMO

Objective: This study aimed to investigate the clinical outcomes of medial opening high tibial osteotomy (MOWHTO) combined with arthroscopic microfracture in the treatment of varus medial compartmental knee osteoarthritis and to assess cartilage regeneration using second-look arthroscopy. Methods: This study involved 86 patients (86 knees) who underwent MOWHTO and microfracture from August 2016 to August 2020, including 15 men and 71 women with an average age of 55.3 ± 7.6 years (range, 42-71 years). The patients underwent a second-look arthroscopy to evaluate the status of cartilage regeneration at the time of plate removal, an average of 2 years after the initial osteotomy. Clinical and radiological examinations were performed preoperatively and at the final follow-up visit. The radiologic evaluation included the weight-bearing line ratio (WBL ratio), mechanical femorotibial angle (FTA), medial proximal tibial angle (MPTA), posterior tibial slope angle (PTS) and Kellgren-Lawrence (KL) grade. Clinical outcomes were assessed using the Knee Society score (KSS) and International Knee Documentation Committee (IKDC) scores. Arthroscopic findings were assessed by macroscopic evaluation of cartilage repair according to the International Cartilage Repair Society (ICRS) grading system. Results: The mean KSS and IKDC scores significantly improved at the final follow-up compared to the scores obtained preoperatively (p < 0.05). At the time of plate removal, a second-look arthroscopic examination showed that the ICRS grade of the medial femoral condyle was as follows: grade I -11 cases, grade II -56, grade III-12, and grade IV-7, and cartilage regeneration was seen in 85% of knees (73/86). The ICRS grade of medial tibial plateau was grade I-12 cases, grade II-44, grade III-22, and grade IV-8, and cartilage regeneration was seen in 63% of knees (54/86). Significant differences were observed between cartilage regeneration and clinical outcomes (p < 0.05). Clinical results were better in the good cartilage regeneration group (grades I and II) than were in the poor cartilage regeneration group (grades III and IV). Conclusion: MOWHTO combined with arthroscopic microfracture can effectively improve clinical outcomes in the treatment of varus medial compartmental knee osteoarthritis. Cartilage regeneration can be promoted by correcting varus deformities, which affect clinical outcomes.

2.
Tissue Cell ; 76: 101759, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35219069

RESUMO

MiR-361-3p has been reported in several types of human cancer. However, the expression profile and biological functions of miR-361-3p in osteosarcoma remain uncovered. The expression profiles of miR-361-3p in osteosarcoma tissues and cell lines were evaluated using RT-qPCR. In 88 osteosarcoma patients, survival analysis was performed using Kaplan-Meier curves; while prognostic significance of miR-361-3p was analyzed using Cox regression analysis. The effects of miR-361-3p on cell proliferation, migration and invasion capacities were analyzed using CCK-8 and transwell assays. The target genes of miR-361-3p were assessed using luciferase reporter assay, RT-qPCR, Western blot and rescue experiments. Xenograft assay was conducted to test tumor growth ability. MiR-361-3p was found to be upregulated in human osteosarcoma tissues and cell lines. The expression of miR-361-3p was observed to be closely associated with TNM stage and lung metastasis. High expression of miR-361-3p was found to be capable of predicting poor clinical prognosis in osteosarcoma patients. Whilst overexpression of miR-361-3p was demonstrated to promote the proliferation, migration and invasion of osteosarcoma cells; knockdown of miR-361-3p was shown to exhibit an opposite inhibitory effect. Bioinformatics analysis and luciferase reporter assays confirmed that ARID3A is a direct target of miR-361-3p. Functional assays demonstrated that osteosarcoma cell proliferation, migration and invasion were promoted by miR-361-3p via negative regulation of ARID3A. Finally, overexpression of ARID3A was shown to partially reverse the tumor-promoting effect of miR-361-3p. Besides, in vivo assays revealed that miR-361-3p overexpression facilitated tumor growth in nude mice. In conclusion, this study indicates that miR-361-3p is a crucial prognostic biomarker of osteosarcoma, and that targeting of miR-361-3p/ARID3A axis may be a promising strategy in osteosarcoma therapy.


Assuntos
Neoplasias Ósseas , Proteínas de Ligação a DNA , MicroRNAs , Osteossarcoma , Fatores de Transcrição , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Carcinogênese , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Curr Med Sci ; 41(4): 777-781, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34403103

RESUMO

OBJECTIVE: Supracondylar humerus fractures are the most frequent fractures of the paediatric elbow. The present study introduced a modified surgical procedure for treatment of supracondylar humerus fractures in children. METHODS: From February 2015 to August 2019, 73 patients with Gartland's type II and III supracondylar fractures were treated with this modified method. Totally, 68 of all patients were followed up for 3-12 months (mean 8.25 months). The evaluation results included fracture nonunion, ulnar nerve injury, pin track infection, carrying angle and elbow joint Flynn score. RESULTS: The results showed that bone union was observed in all children, one case had an iatrogenic ulnar nerve injury, and the symptoms were completely relieved in 4 months after removing of the medial-side pin. All children had no cubitus varus deformity and no pin track infection, and the rate of satisfactory results according to Flynn's criteria score was 100%. CONCLUSION: The modified closed reduction and Kirschner wires internal fixation could effectively reduce the rate of open reduction, the risk of iatrogenic ulnar nerve injury, and the incidence of cubitus varus deformity in treatment of supracondylar humerus fractures in children.


Assuntos
Fixação Interna de Fraturas/métodos , Fraturas do Úmero/cirurgia , Úmero/cirurgia , Procedimentos de Cirurgia Plástica , Fios Ortopédicos , Criança , Pré-Escolar , Feminino , Humanos , Fraturas do Úmero/fisiopatologia , Úmero/fisiopatologia , Masculino , Pediatria
5.
BMC Musculoskelet Disord ; 22(1): 149, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33546657

RESUMO

BACKGROUND: Malignant tumors of the musculoskeletal system, especially osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, pose a major threat to the lives and health of adolescents and children. Current treatments for musculoskeletal tumors mainly include surgery, chemotherapy, and radiotherapy. The problems of chemotherapy resistance, poor long-term outcome of radiotherapy, and the inherent toxicity and side effects of chemical drugs make it extremely urgent to seek new treatment strategies. MAIN TEXT: As a potent gene editing tool, the rapid development of CRISPR/Cas9 technology in recent years has prompted scientists to apply it to the study of musculoskeletal tumors. This review summarizes the application of CRISPR/Cas9 technology for the treatment of malignant musculoskeletal tumors, focusing on its essential role in the field of basic research. CONCLUSION: CRISPR, has demonstrated strong efficacy in targeting tumor-related genes, and its future application in the clinical treatment of musculoskeletal tumors is promising.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Adolescente , Neoplasias Ósseas/genética , Neoplasias Ósseas/terapia , Sistemas CRISPR-Cas/genética , Criança , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Edição de Genes , Humanos , Osteossarcoma/genética , Osteossarcoma/terapia
6.
Drug Des Devel Ther ; 14: 5077-5085, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33239866

RESUMO

PURPOSE: The long-term survival rate of osteosarcoma, which is the most common type of primary malignant bone tumor, has stagnated in past decades. Acacetin is a natural flavonoid compound that has antioxidative and anti-inflammatory effects and exhibits extensive therapeutic effects on various cancers. In this study, the anticancer potential of acacetin and the underlying molecular mechanisms were examined in human osteosarcoma cells (SJSA and HOS). MATERIALS AND METHODS: HOS and SJSA cell lines were exposed to different concentrations of acacetin. Cell proliferation and viability were assessed by CCK-8 and colony-formation assays. Hoechst 33258 fluorescent staining was employed to detect apoptosis. Cell apoptosis was measured by an annexin V-FITC/PI assay by flow cytometry. The alteration in the mitochondrial membrane potential was detected by a JC-1 Assay Kit. Apoptosis-related protein expression was determined by Western blotting. Intracellular reactive oxygen species (ROS) production was detected by fluorescence microscopy and flow cytometry. Subsequently, the activation of the ROS/JNK signaling pathway was investigated. RESULTS: Acacetin could inhibit proliferation and induce apoptosis in SJSA and HOS cells. The acacetin treatment resulted in the activation of caspase-3, -8, and -9 and cleaved PARP. Further studies showed that acacetin-induced apoptosis was attributed to ROS. In addition, we found that acacetin induced the activation of the downstream c-Jun N-terminal kinase (JNK) signaling pathway. Subsequently, after treatment with the ROS scavenger GSH and the JNK inhibitor SP600125, the apoptosis-inducing effect triggered by acacetin was significantly attenuated. CONCLUSION: The results of the present study indicate that acacetin may induce apoptosis to inhibit cell growth by activating the ROS/JNK signaling pathway in SJSA and HOS cells, suggesting that acacetin may be a promising candidate for the management of osteosarcomas.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Flavonas/farmacologia , Osteossarcoma/tratamento farmacológico , Antracenos/farmacologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
7.
Adv Sci (Weinh) ; 6(8): 1801233, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-31016106

RESUMO

Fullerene C60 nanocrystals (nano-C60) possess various attractive bioactivities, including autophagy induction and calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) activation. CaMKIIα is a multifunctional protein kinase involved in many cellular processes including tumor progression; however, the biological effects of CaMKIIα activity modulated by nano-C60 in tumors have not been reported, and the relationship between CaMKIIα activity and autophagic degradation remains unclear. Herein, nano-C60 is demonstrated to elicit reactive oxygen species (ROS)-dependent cytotoxicity and persistent activation of CaMKIIα in osteosarcoma (OS) cells. CaMKIIα activation, in turn, produces a protective effect against cytotoxicity from nano-C60 itself. Inhibition of CaMKIIα activity by either the chemical inhibitor KN-93 or CaMKIIα knockdown dramatically promotes the anti-OS effect of nano-C60. Moreover, inhibition of CaMKIIα activity causes lysosomal alkalinization and enlargement, and impairs the degradation function of lysosomes, leading to autophagosome accumulation. Importantly, excessive autophagosome accumulation and autophagic degradation blocking are shown to play an important role in KN-93-enhanced-OS cell death. The synergistic anti-OS efficacy of KN-93 and nano-C60 is further revealed in an OS-xenografted murine model. The results demonstrate that CaMKIIα inhibition, along with the suppression of autophagic degradation, presents a promising strategy for improving the antitumor efficacy of nano-C60.

8.
Cell Death Dis ; 9(9): 902, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185772

RESUMO

Since publication of this article, the authors have noticed errors in Fig. 1e (the merge image of control group) and Fig. 5e (Pec. 50 mg/kg group). As a result of the misfiling of the data, incorrect images were inadvertently inserted in Figs. 1e and 5e during figure preparation. The correct figures are given below.

10.
Cell Death Dis ; 8(9): e3048, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28906492

RESUMO

Combretastatin A-4 (CA-4), a tubulin-depolymerizing agent, shows promising antitumor efficacy and has been under several clinical trials in solid tumors for 10 years. Autophagy has an important pro-survival role in cancer therapy, thus targeting autophagy may improve the efficacy of antitumor agents. N-myc downstream-regulated gene 1 (NDRG1) is a significant stress regulatory gene, which mediates cell survival and chemoresistance. Here we reported that CA-4 could induce cell-protective autophagy, and combination treatment of CA-4 and autophagy inhibitor chloroquine (CQ) exerted synergistic cytotoxic effect on human osteosarcoma (OS) cells. Meanwhile, CA-4 or CQ could increase the expression of NDRG1 independently. We further performed mechanistic study to explore how CA-4 and CQ regulate the expression of NDRG1. Using luciferase reporter assay, we found that CA-4 transcriptionally upregulated NDRG1 expression, whereas CQ triggered colocalization of NDRG1 and lysosome, which subsequently prevented lysosome-dependent degradation of NDRG1. Further, we showed that knockdown of NDRG1 caused the defect of lysosomal function, which accumulated LC3-positive autophagosomes by decreasing their fusion with lysosomes. Moreover, NDRG1 inhibition increased apoptosis in response to combination treatment with CA-4 and CQ. Taken together, our study revealed abrogation of NDRG1 expression sensitizes OS cells to CA-4 by suppression of autophagosome-lysosome fusion. These results provide clues for developing more effective cancer therapeutic strategies by the concomitant treatment with CA-4 and clinical available autophagy inhibitors.


Assuntos
Autofagia , Proteínas de Ciclo Celular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Estilbenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Fusão de Membrana , Modelos Biológicos , Osteossarcoma/genética , Estilbenos/farmacologia , Regulação para Cima/efeitos dos fármacos
11.
Mol Med Rep ; 16(2): 1347-1352, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28627658

RESUMO

Osteosarcoma is the most common primary malignant bone tumor. Cancer cells employ a host of mechanisms to develop resistance to adriamycin (ADM) or other chemotherapeutic drugs. Shikonin (SK), an active constituent extracted from a Chinese medicinal herb, has been shown to cooperate with ADM in the treatment of osteosarcoma and certain other types of cancer by contributing to the response rate of chemotherapy and the side effects. The aim of the present study was to investigate the role and underlying mechanism of SK in chemotherapy for osteosarcoma. In the present study, a CCK-8 assay was performed to assess cell survival rate in vitro. Western blot analysis was performed to determine the expression levels of B­cell lymphoma 2­associated X protein (Bax), caspase­3, caspase­8, and poly (ADP­ribose) polymerase (PARP). Flow cytometry was used to analyze cell cycle and cell death. The survival rate of cells decreased significantly in a dose­ and time­dependent manner when treated with a combination of SK and ADM. Western blot analysis revealed increased expression levels of Bax, caspase­3, caspase­8 and PARP in U2OS and MG63 cells 48 h following treatment with SK and ADM. Flow cytometric analysis showed that the combined treatment of SK and ADM significantly induced apoptosis in the osteosarcoma cells. Taken together SK cooperated with ADM to promote apoptosis, possibly by inducing caspase­3­ and caspase­8­dependent apoptosis. SK may be a potential enhancer in the treatment of drug­resistant primary osteosarcoma.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/metabolismo , Caspase 3/metabolismo , Caspase 8/metabolismo , Doxorrubicina/farmacologia , Naftoquinonas/farmacologia , Osteossarcoma/metabolismo , Neoplasias Ósseas/genética , Caspase 3/genética , Caspase 8/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Osteossarcoma/genética
12.
Free Radic Biol Med ; 106: 24-37, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28188923

RESUMO

Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25-30 years. Arsenic sulfide (As2S2), the main active ingredient of the traditional Chinese medicine realgar, has been proved to have antitumor efficacy in several tumor types including acute promyelocytic leukemia, gastric cancer and colon cancer. Here, we investigated the efficacy and mechanism of As2S2 in osteosarcoma both in vitro and in vivo. In this study, we demonstrated that As2S2 potently suppressed cell proliferation by inducing G2/M phase arrest in various osteosarcoma cell lines. Also, treatment with As2S2 induced apoptosis and autophagy in osteosarcoma cells. The apoptosis induction was related to PARP cleavage and activation of caspase-3, -8, -9. As2S2 was demonstrated to induce autophagy as evidenced by formation of autophagosome and accumulation of LC3II. Further studies showed that As2S2-induced apoptosis and autophagy could be significantly attenuated by ROS scavenger and JNK inhibitor. Moreover, we found that As2S2 inhibited Akt/mTOR signaling pathway, and suppressing Akt and mTOR kinases activity can increase As2S2-induced apoptosis and autophagy. Finally, As2S2in vivo suppressed tumor growth with few side effects. In summary, our results revealed that As2S2 induced G2/M phase arrest, apoptosis, and autophagy via activing ROS/JNK and blocking Akt/mTOR signaling pathway in human osteosarcoma cells. Arsenic sulfide may be a potential clinical antitumor drugs targeting osteosarcoma.


Assuntos
Arsenicais/administração & dosagem , Proteína Oncogênica v-akt/genética , Osteossarcoma/tratamento farmacológico , Sulfetos/administração & dosagem , Serina-Treonina Quinases TOR/genética , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Caspases/biossíntese , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Medicina Tradicional Chinesa , Camundongos , Osteossarcoma/genética , Osteossarcoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Cell Mol Med ; 21(2): 208-221, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27624867

RESUMO

Osteosarcoma (OS) is the most frequent primary malignant bone tumour. Alternol, a novel compound purified from microbial fermentation products exerts anti-tumour effects across several cancer types. The effect of alternol on human OS remains to be elucidated. We first evaluated the anti-tumour effect of alternol in several human OS cell lines in vitro and investigated its underlying mechanism. Alternol inhibited OS cell proliferation, migration and induced caspase-dependent apoptosis, G2/M cell cycle arrest in a dose and time-dependent manner. Moreover, alternol treatment inhibited signal transducer and activator of transcription-3 (STAT3) phosphorylation in 143B and MG63 human OS cells, as evaluated using a STAT3-dependent dual luciferase reporter system. Exposure to alternol resulted in excessive reactive oxygen species (ROS) generation and Jun amino-terminal kinases (JNK), extracellular signal-regulated kinases (ERK1/2) and p38 activation. Furthermore, alternol-induced cell death was significantly restored in the presence of the ROS scavenger, N-acetyl-l-cysteine (NAC) or a caspase inhibitor Z-VAD-FMK. NAC also prevented G2/M phase arrest and phosphorylation of mitogen-activated protein kinases (MAPK), but did not reverse STAT3 inactivation. Finally, alternol suppressed tumour growth in vivo in the nude mouse OS tibia orthotopic model. Immunohistochemistry revealed that alternol treatment resulted in down-regulation of phosph-STAT3 Tyr705 and up-regulation of cleaved caspase-3 and phosph-SAPK (Stress-activated protein kinases)/JNK expression. Taken together, our results reveal that alternol suppresses cell proliferation, migration and induces apoptosis, cell cycle arrest by modulating of ROS-dependent MAPK and STAT3 signalling pathways in human OS cells. Therefore, alternol is a promising candidate for developing anti-tumour drugs target OS.


Assuntos
Antineoplásicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Sistema de Sinalização das MAP Quinases , Osteossarcoma/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Produtos Biológicos/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Fatores de Tempo
14.
Cell Death Dis ; 7(10): e2421, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27735939

RESUMO

Signal transducer and activator of transcription 3 (STAT3) has important roles in cancer aggressiveness and has been confirmed as an attractive target for cancer therapy. In this study, we used a dual-luciferase assay to identify that pectolinarigenin inhibited STAT3 activity. Further studies showed pectolinarigenin inhibited constitutive and interleukin-6-induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus and blocked STAT3 DNA-binding activity in osteosarcoma cells. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNA methyltransferase 1/HDAC1 histone deacetylase 1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma cell proliferation, induced apoptosis and reduced the level of STAT3 downstream proteins cyclin D1, Survivin, B-cell lymphoma 2 (Bcl-2), B-cell lymphoma extra-large (Bcl-xl) and myeloid cell leukemia 1 (Mcl-1). In addition, pectolinarigenin inhibited migration, invasion and reserved epithelial-mesenchymal transition (EMT) phenotype in osteosarcoma cells. In spontaneous and patient-derived xenograft models of osteosarcoma, we identified administration (intraperitoneal) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and impaired tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity.


Assuntos
Produtos Biológicos/farmacologia , Cromonas/farmacologia , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Produtos Biológicos/toxicidade , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromonas/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Invasividade Neoplásica , Fenótipo , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Análise de Sobrevida , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Oncotarget ; 7(37): 60623-60638, 2016 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-27556355

RESUMO

CD151, a tetraspanin family protein involved in cell-cell and cell-extracellular matrix interaction, is differentially expressed in osteosarcoma cell membranes. Thus, this study aimed to investigate the role of CD151 in osteosarcoma metastasis. We analyzed CD151 expression in patient tissue samples using immunohistochemistry. CD151 expression was also silenced with shRNA in osteosarcoma cells of high metastatic potential, and cell adhesion, migration and invasion were evaluated in vitro and pulmonary metastasis was investigated in vivo. Mediators of cell signaling pathways were also examined following suppression of CD151 expression. Overall survival for patients with low versus high CD151 expression level was 94 vs. 41 months (p=0.0451). CD151 expression in osteosarcoma cells with high metastatic potential was significantly higher than in those with low metastatic potential (p<0.001). shRNA-mediated silencing of CD151 did not influence cell viability or proliferation; however, cell adhesion, migration and invasion were all inhibited (all p<0.001). In mice inoculated with shRNA-transduced osteosarcoma cells, the number and size of lung metastatic lesions were reduced compared to the mice inoculated with control-shRNA transduced cells (p<0.001). In addition, CD151 knockdown significantly reduced Akt, p38, and p65 phosphorylation as well as focal adhesion kinase, integrin ß1, p70s6, and p-mTOR levels. Taken together, CD151 induced osteosarcoma metastasis likely by regulating cell function through adhesion signaling. Further studies are necessary to fully explore the diagnostic and prognostic value of determining CD151 expression in osteosarcoma patients.


Assuntos
Neoplasias Pulmonares/metabolismo , Osteossarcoma/metabolismo , Tetraspanina 24/metabolismo , Animais , Adesão Celular , Movimento Celular , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Nus , Osteossarcoma/mortalidade , Osteossarcoma/patologia , RNA Interferente Pequeno/genética , Transdução de Sinais , Análise de Sobrevida , Tetraspanina 24/genética , Análise Serial de Tecidos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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