Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Hedgehog pathway functions as an organizer in embryonic development. Aberrant activation of the Hedgehog pathway has been reported in various types of malignant tumours. The GLI2 transcription factor is a key mediator of Hedgehog pathway but its contribution to neoplasia is poorly understood. To establish the role of GLI2 in osteosarcoma, we examined its expression by real-time PCR using biopsy tissues. To examine the function of GLI2, we evaluated the growth of osteosarcoma cells and their cell cycle after GLI2 knockdown. To study the effect of GLI2 activation, we examined mesenchymal stem cell growth and the cell cycle after forced expression of GLI2. We found that GLI2 was aberrantly over-expressed in human osteosarcoma biopsy specimens. GLI2 knockdown by RNA interferences prevented osteosarcoma growth and anchorage-independent growth. Knockdown of GLI2 promoted the arrest of osteosarcoma cells in G(1) phase and was accompanied by reduced protein expression of the cell cycle accelerators cyclin D1, SKP2 and phosphorylated Rb. On the other hand, knockdown of GLI2 increased the expression of p21(cip1) . In addition, over-expression of GLI2 promoted mesenchymal stem cell proliferation and accelerated their cell cycle progression. Finally, evaluation of mouse xenograft models showed that GLI2 knockdown inhibited the growth of osteosarcoma in nude mice. Our findings suggest that inhibition of GLI2 may represent an effective therapeutic approach for patients with osteosarcoma.
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PMID:Role of GLI2 in the growth of human osteosarcoma. 2150 30

Cyclin proteins in association with cyclin-dependent protein kinase (Cdk) subunits function to execute critical cell cycle transitions; dysregulation of these enzymes may play a pivotal role in human tumorigenesis. In this study we characterize the successive expression of cyclins D1, E, A, and B, as well as a novel cyclin-like protein, in synchronized human MG-63 osteosarcoma cells. The physiological activation, subunit configuration, and subcellular localization of cyclin D1 during the G1 phase of the cell cycle is characterized in additional detail. An essential role for cyclin D1 in osteosarcoma cell proliferation is inferred by the efficacy of an antisense oligo-deoxynucleotide strategy directed against this locus. In addition, we report on the amplification and comparative over-expression of cyclin D1 in a Ewing's sarcoma cell line. These findings support a sequential model of cyclin expression and suggest that examination of the levels of specific cyclins may provide valuable diagnostic and/or prognostic information in the evaluation of proliferative disorders.
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PMID:Sequential and progressive cyclin expression in human osteosarcoma cells - diagnostic and therapeutic implications. 2157 44

Osteosarcoma, which is the most common primary bone tumor, occurs most frequently in adolescents. A number of studies have indicated that plumbagin (PL) (5-hydroxy-2-methyl-1, 4-naphthoquinone), a compound found in the plants of the Plumbaginaceae and Droseraceae families, possesses anticancer activity. However, its anticancer effects and mechanisms against osteosarcoma have not been explored. To determine the anticancer effect of PL on osteosarcoma cell lines MG-63 and U2OS, cell viability, apoptosis, cell cycle distribution, caspase-3 and caspase-9 activity and intracellular reactive oxygen species (ROS) generation were measured, and Western blot analyses were performed. PL significantly inhibited the growth of osteosarcoma cells, particularly U2OS cells. PL up-regulated the expression of p53 in U2OS cells and p21 in the two osteosarcoma cell lines causing cell cycle arrest by decreasing the expression of murine double minute 2 (MDM2)/cyclin B1 and cyclin D1. Furthermore, PL altered the ratio of Bax/Bcl-2, and may have triggered the mitochondrial apoptotic pathway, resulting in caspase-3 and caspase-9 activation. We also found that PL induced the generation of ROS in osteosarcoma cell lines. To conclude, PL exerted anticancer activity on osteosarcoma cells by inducing pro-apoptotic signaling and modulating the intracellular ROS that causes induction of apoptosis. These effects may relate to the p53 status.
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PMID:Plumbagin induces apoptosis via the p53 pathway and generation of reactive oxygen species in human osteosarcoma cells. 2199 62

Elucidation of the molecular mechanisms of leukemogenesis is important for a better understanding of the prognosis of acute lymphoblastic leukemia (ALL). Studies have shown that the expression of upregulated gene 4 (URG4), which promotes cell growth and survival, is increased in different types of carcinomas including hepatocellular carcinoma, gastric cancer and osteosarcoma. Similarly, higher expression of URG4 and cyclin D1 gene might promote proliferation of the blast cells by causing escape from the G1 checkpoint and entry into the S phase. This study reports the high expression level of URG4 in 2 high-risk ALL patients for the first time in the literature. In conclusion, the higher expression of URG4 in our 2 patients suggests that URG4 might be involved in leukemogenesis. Future studies with a large number of high-risk ALL patients and cell culture studies are needed to demonstrate the exact role of URG4 in leukemogenesis.
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PMID:Higher expression of the novel gene upregulated gene 4 in two acute lymphoblastic leukemia patients with poor prednisolone response. 2267 19

TRAF6, a unique tumor necrosis factor receptor-associated factor (TRAF) family member, possesses a unique receptor-binding specificity that results in its crucial role as the signaling mediator for TNF receptor superfamily and interleukin-1 receptor/Toll-like receptor superfamily. TRAF6 plays an important role in tumorigenesis, invasion and metastasis. This study aimed to explore the expression of TRAF6 in osteosarcoma tissues and its correlation to the clinical pathology of osteosarcoma and to discuss the relationship between TRAF6 expression and osteosarcoma invasion. These data will provide the experimental base for the biological treatment of osteosarcoma in the future. Using RT-PCR and Western blot, the results showed that the expression rate of TRAF6 mRNA in osteosarcoma tissues was significantly higher than that in normal bone tissue (p < 0.05), that the expression rate of TRAF6 mRNA in the carcinoma tissues from patients with lung metastasis was significantly higher than that from patients without lung metastasis (p < 0.05), and that the expression rate of TRAF6 mRNA also increased with increasing Enneking stage (p < 0.05). However, the mRNA expression of TRAF6 in osteosarcoma was independent of the patient's gender, age, and tumor size (p > 0.05). The TRAF6 protein displayed an up-regulation in osteosarcoma tissues compared to normal bone tissue (p < 0.05), displayed an up-regulation in osteosarcoma tissues from patients with lung metastasis compared to from patients without lung metastasis (p < 0.05), and displayed a gradual increase with increasing Enneking stage (p < 0.05). By the technique of RNA interference, the expression of TRAF6 in the human osteosarcoma MG-63 cell line was down-regulated, and the invasive ability of MG-63 cells was examined. The results showed that TRAF6 protein expression was significantly decreased in the MG-63 cells from TRAF6 siRNA-transfected group (p < 0.05), and the proliferation ability of MG-63 cells and the number of MG-63 cells that passed through the Transwell chamber were significantly lower than that in the non-transfected control group as well as the transfected control group (p < 0.05). In addition, the percentage of MG-63 cells undergoing apoptosis was significantly higher in the TRAF6 siRNA-transfected group compared with the non-transfected control group as well as the transfected control group (p < 0.05). The expression of p-p65, cyclin D1, MMP-9 was down-regulated in the MG-63 cells from TRAF6 siRNA-transfected group. The expression of caspase 3 was up-regulated in the MG-63 cells from TRAF6 siRNA-transfected group compared to the non-transfected control group as well as the transfected control group (p < 0.05). To make a long story short, the overexpression of TRAF6 in osteosarcoma might be related to the tumorigenesis, invasion of osteosarcoma.
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PMID:TRAF6 regulates proliferation, apoptosis, and invasion of osteosarcoma cell. 2288 93

Osteosarcoma, the most common primary tumor of the bones, causes many deaths due to its rapid proliferation and drug resistance. Recent studies have shown that cyclin D1 plays a key regulatory role during cell proliferation, and non-coding microRNAs (miRNAs) act as crucial modulators of cyclin D1 (CCND1). The aim of the current study was to determine the role of miRNAs in controlling CCND1 expression and inducing cell apoptosis. CCND1 has been found to be a target of miR-15a and miR-16-1 through analysis of complementary sequences between microRNAs and CCND1 mRNA. The upregulation of miR-15a and miR-16-1 in the cell line SOSP-9607 induces apoptosis and cell cycle arrest. Osteosarcoma cells transfected with miR-15a and miR-16-1 show slower proliferation curves. Moreover, the transcription of CCND1 is suppressed by miR-15a and miR-16-1 via direct binding to the CCND1 3'-untranslated region (3'-UTR). The data presented here demonstrate that the CCND1 contributes to osteosarcoma cell proliferation, suggesting that repression of CCND1 by miR-15a and miR-16-1 could be used for osteosarcoma therapy.
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PMID:miR-15a and miR-16-1 downregulate CCND1 and induce apoptosis and cell cycle arrest in osteosarcoma. 2292 27

SASH1, a member of the SLY-family of signal adapter proteins, is a candidate tumor suppressor in breast and colon cancer. The SASH1 protein possesses both the SH3 and SAM domains, indicating that it may play an important role in intracellular signal transduction. Reduced expression of SASH1 is closely related to tumor growth, invasion, metastasis, and poor prognosis. However, the biological role of SASH1 remains unknown in osteosarcoma. To unravel the function of SASH1, we explored the expression of SASH1 in osteosarcoma tissues and its correlation to the clinical pathology of osteosarcoma and analyzed the relationship between SASH1 expression and cell cycle, apoptosis and invasion of osteosarcoma MG-63 cells, using the flow cytometry analysis and transwell invasion chamber experiments. Furthermore, the effect of SASH1 on the expression of cyclin D1, caspase-3, matrix metalloproteinase (MMP)-9 were observed by western blot. Our results showed that the expression rate of SASH1 mRNA in osteosarcoma tissues was significantly lower than that in normal bone tissue (p = 0.000), that the expression rate of SASH1 mRNA in the carcinoma tissues from patients with lung metastasis was significantly lower than that from patients without lung metastasis (p = 0.041), and that the expression rate of SASH1 mRNA also decreased with increasing Enneking stage (p = 0.032). However, the mRNA expression of SASH1 in osteosarcoma was independent of the patient's gender, age, and tumor size (p = 0.983, 0.343, 0.517, respectively). The SASH1 protein displayed a down-regulation in osteosarcoma tissues compared to normal bone tissue (p = 0.000), displayed a down-regulation in osteosarcoma tissues from patients with lung metastasis compared to from patients without lung metastasis (p = 0.000), and displayed a gradual decrease with increasing Enneking stage (p = 0.000). In addition, the MG-63 cells from pcDNA3.1-SASH1 group exhibited significantly reduced cell viability, proliferation, and invasive ability compared to the empty vector group and blank control group (p = 0.023, 0.001, respectively), and there was no difference between the empty vector group and blank control group. The pcDNA3.1-SASH1 group displayed significantly more apoptotic cells than the empty vector group and blank control group (p = 0.004). The expression of cyclin D1, MMP-9 displayed a down-regulation in MG-63 cells from pcDNA3.1-SASH1 group compared to the empty vector group and blank control group (p = 0.000, 0.001, respectively) and the expression levels of caspase-3 displayed an up-regulation in MG-63 cells from pcDNA3.1-SASH1 group compared to the empty vector group and blank control group (p = 0.000). Taken together, these data indicated that the overexpression of SASH1 might be associated with the inhibition of growth, proliferation, and invasion of MG-63 cells and the promotion of apoptosis of MG-63 cells.
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PMID:SASH1 regulates proliferation, apoptosis, and invasion of osteosarcoma cell. 2310 92

Baicalein is a bioactive flavonoid that is widely used in ancient China. However, its effects on the most common primary malignant bone tumor, osteosarcoma, remain unknown. In the present study, we investigated the effects of baicalein in osteosarcoma cells. Our results indicate baicalein might be an efficacious anti-osteosarcoma drug. We found that baicalein could inhibit cell proliferation in a time- and dose-dependent manner. Additionally, we demonstrated that baicalein promotes osteosarcoma cell apoptosis, and our mechanistic studies suggest that this is mediated by caspase activation, especially caspase-3. We also showed that the down-regulation of Bcl-2 and concurrent increase in Bax and Bim levels contribute to the apoptosis induced by baicalein. In addition, we observed that baicalein induces G1 cell cycle arrest by decreasing cyclin D1 and cyclin-dependent kinase 4 (CDK4). Furthermore, our data verifies that baicalein can reduce osteosarcoma cell adhesion, migration and invasion in vitro, which indicates its potential to inhibit osteosarcoma metastasis. The decrease in expression of matrix metalloproteinases (MMP)-2 and MMP-9 may contribute to the effects of baicalein. Taken together, our results provide evidence that baicalein plays important roles in anti-osteosarcoma therapy, and thus may serve as a novel and efficient candidate agent for osteosarcoma treatment.
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PMID:Effects of baicalein on apoptosis, cell cycle arrest, migration and invasion of osteosarcoma cells. 2326 3

It seems established that the onset of osteosarcoma and the reduction in melatonin production run in parallel; this suggests that the decline in the cancer-inhibiting agent, melatonin, may contribute to the occurrence of osteosarcoma and that melatonin supplementation may have promise for preventing the development and progression of this condition. There is, however, no direct evidence regarding an antiproliferative effect of melatonin in osteosarcoma cells. In the current study, we examined whether melatonin inhibits the proliferation of human osteosarcoma cell line MG-63. MTT staining showed that at 4 mM-10 mM concentrations, melatonin significantly reduced the MG-63 cell proliferation in a dose-dependent and time-dependent manner. Flow cytometry documented that 4 mM melatonin significantly increased the fraction of cells in the G(0)/G(1) phase of the cell cycle, while simultaneously reducing the proportion in the S and G(2)/M phases. Western blot and real-time PCR analyses further confirmed that melatonin's inhibitory effect was possibly because of downregulation of cyclin D1 and CDK4, related to the G(1) phase, and of cyclin B1 and CDK1, related to the G(2)/M phase. There was no downregulation of cyclin E, CDK2, and cyclin A, which are related to G(1)/S transition and S phase. These findings provide evidence that melatonin may significantly inhibit human osteosarcoma cell proliferation in a dose-dependent and time-dependent manner and this inhibition involves the downregulation of cyclin D1, CDK4, cyclin B1 and CDK1.
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PMID:Melatonin inhibits the proliferation of human osteosarcoma cell line MG-63. 2347 Aug 34

Epirubicin is widely used in osteosarcoma chemotherapy. Growing evidence indicates that the microRNA (miRNA) expression levels which are induced by chemotherapeutic agents play an important role in osteosarcoma development and progression. In this study we investigate the alterations of miRNA expression in the osteosarcoma cells after epirubicin treatment and whether miRNAs can enhance its anti-osteosarcoma effect. After epirubicin exposure, microarray shows 40 miRNAs are differentially expressed in osteosarcoma cells including 24 down-regulated miRNAs. Notably, miR-302b, which is stably low-expressed in osteosarcoma, could be induced by the epirubicin. Furthermore, we find that miR-302b can inhibit the osteosarcoma cell proliferation, promote cell apoptosis and cell cycle arrest MiR-302b can activate caspase-3 and regulate the Akt/pAkt, Bcl-2, Bim expression to increase the cell apoptosis. Meanwhile, miR-302b also attenuates cyclin D1 and CDKs expression to induce cell cycle arrest. Therefore, our results suggest miR-302b can play an essential role in osteosarcoma treatment as a potential tumor suppressor.
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PMID:Epirubicin-mediated expression of miR-302b is involved in osteosarcoma apoptosis and cell cycle regulation. 2384 51


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