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

A number of recent studies suggest that mitochondrial function is a player in tumor development and progression. In this study, we have used gene expression arrays to examine transcriptional differences between oxidative phosphorylation (OXPHOS)-competent and OXPHOS-impaired human osteosarcoma cells. Genes associated with extracellular matrix remodeling, including members of the matrix metalloproteinases (MMPs) and tissue inhibitors of the MMP (TIMP) family, urokinase plasminogen activator and its inhibitor plasminogen-activator inhibitor-1 (PAI1), and CTGF and CYR61 (members of the Cysteine-rich 61, Connective Tissue Growth Factor and Nephroblastoma-overexpressed (CCN) gene family of growth regulators), were among the ones significantly altered in the OXPHOS-deficient cells. These changes were confirmed by RT-PCR and promoter reporter assays. Alterations at the protein level for some of these factors were also observed, though at a lower magnitude, with the exception of TIMP1, where a marked change in steady-state levels of the protein was observed after induction of OXPHOS dysfunction. Repopulation of mitochondrial DNA (mtDNA)-less cells with wild-type mtDNA reduced matrigel invasion, whereas repopulation with a mutated mtDNA did not. Taken together our data suggests that OXPHOS dysfunction modulates the invasive phenotype by transcriptional regulation of genes coding for members of the MMP/TIMP system, urokinase plasminogen activator/plasminogen-activator inhibitor I and CCN proteins.
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PMID:Oxidative phosphorylation dysfunction modulates expression of extracellular matrix--remodeling genes and invasion. 1622 32

Numerous studies have demonstrated a correlation of matrix metalloproteinase (MMP) overexpression with the prognosis of various kinds of cancer. The current study investigated whether the expression of MMPs is correlated with the prognosis of osteosarcoma. Expression levels of MMP-2, -9, MT1-MMP and TIMP-2 were examined immunohistochemically in samples from 47 patients with osteosarcoma. Correlation of the positivity of staining with prognosis was analyzed with the Kaplan-Meier method, and statistically analyzed with log-rank test. Co-localization of MMP-2, MT1-MMP and TIMP-2 was determined by double staining with fluorescence-conjugated antibodies. Activities of gelatinases in representative tissues were examined with gelatin zymography. MMP-2 was expressed strongly in 60% of cases (28/47), and MMP-9, MT1- MMP and TIMP-2 was strongly positive in 61% (29/47), 45% (21/47), and 91% (43/47), respectively. Increased MT1-MMP expression was associated significantly with poor prognosis in overall survival (P=0.0480). In cases of overexpression for both MMP-2 and MT1-MMP, there was a tendency for poor prognosis (P=0.0969). In 36 cases who underwent neoadjuvant chemotherapy, wide resection of the tumors and post-operative adjuvant chemotherapy, increased expression of MT1-MMP resulted in a significant negative prognostic factor for disease-free survival (P=0.0143). Also, co-overexpression of MT1-MMP and MMP-2 showed a tendency to correlate to the reduced disease-free survival (P=0.0502). Increased gelatinase activity was observed in tissues of co-overexpression of MT1-MMP and MMP-2. The results of this study demonstrate the correlation of MT1-MMP expression and the oncological outcome of osteosarcoma patients, suggesting the prognostic significance of these proteins in osteosarcoma patients.
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PMID:Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma. 1632 77

In the present study, we have investigated the effect of (i) ET-1 (endothelin-1) and its precursor, big ET-1, on MMP (matrix metalloproteinase)-2 and MMP-9 synthesis and activity in osteosarcoma tissue, and (ii) ET-1 receptor antagonists on cell invasion. Using Western blotting, zymography, RT-PCR (reverse transcription-PCR), immunohistochemistry, immunofluorescence and Northern blotting, we have shown that ET-1 and ET-1 receptors (ET(A) and ET(B)) were expressed in these cells. Additionally, we have demonstrated that ET-1 markedly induced the synthesis and activity of MMP-2, which was significantly increased when compared with MMP-9. Furthermore, inhibition of NF-kappaB (nuclear factor kappaB) activation blocked MMP-2 production and activity, indicating the involvement of NF-kappaB, a ubiquitous transcription factor playing a central role in the differentiation, proliferation and malignant transformation. Since ET-1 acts as an autocrine mediator through gelatinase induction and because inhibition of ET(A) receptor is beneficial for reducing both basal and ET-1-induced osteosarcoma cell invasion, targeting this receptor could be an attractive therapeutic alternative for the successful treatment of osteosarcoma.
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PMID:Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-kappaB in human osteosarcoma. 1641 66

Silibinin is a natural flavonoid antioxidant with anti-hepatotoxic properties and pleiotropic anticancer capabilities. We tested the hypothesis that silibinin inhibits cellular invasiveness by down-regulating the focal adhesion kinase (FAK) and extracellular signal-regulated protein kinase (ERK)-dependent c-Jun/activator protein-1 (AP-1) induction, which leads to inhibition of urokinase-type plasminogen activator (u-PA) and matrix metalloproteinase-2 (MMP-2) expressions in human osteosarcoma MG-63 cells. We found that silibinin decreased cell adhesion and invasiveness, as well as inhibited u-PA and MMP-2 expressions. Silibinin reduced ERK 1/2 phosphorylation, but had no effects on the phosphorylation of c-Jun N-terminal kinases (JNKs) 1/2, p38 and Akt. Silibinin suppressed AP-1-binding activity and c-Jun levels and its phosphorylation without changes of c-Fos and Ets-1 levels. Silibinin also inhibited interleukin-6-induced ERK 1/2 and c-Jun phosphorylation, and cell invasiveness. Thus, silibinin may possess an anti-metastatic activity in MG-63 cells.
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PMID:Silibinin suppresses human osteosarcoma MG-63 cell invasion by inhibiting the ERK-dependent c-Jun/AP-1 induction of MMP-2. 1711 26

We previously reported the Wnt receptor low-density lipoprotein receptor-related protein 5 (LRP5) was frequently expressed in osteosarcoma (OS) tissue and correlated with metastasis and a lower disease-free survival. Subsequent in vitro analysis revealed that dominant-negative, soluble LRP5 (sLRP5) can reduce in vitro cellular invasion. In the current study, we examined the molecular mechanisms of blocking canonical Wnt signaling by sLRP5 in Saos-2 osteosarcoma cells. Transfection of sLRP5 caused a marked up-regulation of E-cadherin in this cell line. This increase in E-cadherin, seen primarily at the cell-cell contact borders, was associated with down-regulation of Slug and Twist, transcriptional repressors which mediate cancer invasion and metastasis. In contrast, N-cadherin, a mesenchymal marker, was reduced by sLRP5. In addition, blocking Wnt signaling by sLRP5 modulated other epithelial and mesenchymal markers (keratin 8 and 18, fibronectin), suggesting a reversal of epithelial-mesenchymal transition (EMT) seen during cancer progression. SLRP5 also reduced the expression of matrix metalloproteinase (MMP) 2 and 14, consistent with a decrease in invasive capacity. SLRP5 transfection decreased both Met expression and hepatocyte growth factor (HGF)-induced cell motility. Taken together, these results support a role for Wnt/LRP5 signaling in invasiveness of a subset of OS cells.
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PMID:Blocking Wnt/LRP5 signaling by a soluble receptor modulates the epithelial to mesenchymal transition and suppresses met and metalloproteinases in osteosarcoma Saos-2 cells. 1731

Mouse FBJ virus-induced osteosarcoma FBJ-S1 cells rich in GD1a are not readily metastatic, whereas FBJ-LL cells with low levels of GD1a are highly metastatic. GD1a was previously shown to suppress metastasis of mouse FBJ cells and to upregulate caveolin-1 and stromal interaction molecule 1 expression. The present study demonstrates that matrix metalloproteinase-9 (MMP-9) expression renders FBJ-LL cells invasive. MMP-9 is inversely regulated by GD1a, based upon four observations: MMP-9 mRNA content was 5 times higher in FBJ-LL cells than FBJ-S1 cells; a GD1a-re-expressing FBJ-LL cell variant produced through beta1,4GalNAcT-1 cDNA transfection expressed lower levels of MMP-9; exogenous addition of GD1a to FBJ-LL cells decreased MMP-9 production in a dose- and time-dependent manner; and treatment of GD1a-rich cells with D-PDMP or siRNA targeting St3gal2 decreased GD1a expression, but augmented MMP-9 expression. This is the first report demonstrating that GD1a negatively regulates expression of MMP-9 at the transcriptional level.
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PMID:Ganglioside GD1a negatively regulates matrix metalloproteinase-9 expression in mouse FBJ cell lines at the transcriptional level. 1765 76

Osteosarcoma is the most common primary bone tumor, but the pathogenesis is not well understood. While cyclooxygeanse-2 (COX-2) is known to be closely associated with tumor growth and metastasis in several kinds of human tumors, the function of COX-2 in osteosarcoma is unclear. Therefore, to investigate the function of COX-2 in osteosarcoma, we established stable cell lines overexpressing COX-2 in U2OS human osteosarcoma cells. COX-2 overexpression as well as prostaglandin E2 treatment promoted proliferation of U2OS cells. In addition, COX-2 overexpression enhanced mobility and invasiveness of U2OS cells, which was accompanied by increases of matrix metalloproteinase-2 and -9 (MMP-2 and -9) activities. Selective COX-2 inhibitors, NS-398 and celecoxib, inhibited cell proliferation and abrogated the enhanced mobility, invasiveness and MMP activities induced by COX-2 overexpression. These results suggest that COX-2 is directly associated with cell proliferation, migration and invasion in human osteosarcoma cells, and the therapeutic value of COX-2 inhibitors should be evaluated continuously.
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PMID:Cyclooxygenase-2 promotes cell proliferation, migration and invasion in U2OS human osteosarcoma cells. 1793 34

Osteosarcoma (OS) is a primary malignant bone tumor with a high propensity for local recurrence and distant metastasis. We previously showed a secreted, dominant-negative LRP5 receptor (DNLRP5) suppressed in vitro migration and invasion of the OS cell line SaOS-2. Therefore, we hypothesized DNLRP5 also has in vivo antitumor activity against OS. We used the 143B cell line as a model to study the effect of DNLRP5 by stable transfection. Inhibition of Wnt signaling by DNLRP5 was verified by a reduction in TOPFLASH luciferase activity. In soft agar, DNLRP5-transfected 143B cells formed fewer and smaller colonies than control transfected cells. DNLRP5 transfection reduced in vivo tumor growth of 143B cells in nude mice. DNLRP5 also decreased in vitro cellular motility in a scratch wound assay. In a spontaneous pulmonary metastasis model, DNLRP5 reduced both the size and number of lung metastatic nodules. The reduction in cellular invasiveness by DNLRP5 was associated with decreased expression of matrix metalloproteinase-2, N-cadherin, and Snail. Our data suggest canonical Wnt/LRP5 signaling reflects an important underlying mechanism of OS progression. Therefore, strategies to suppress LRP5-mediated signaling in OS cells may lead to a reduction in local or systemic disease burden.
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PMID:Dominant negative LRP5 decreases tumorigenicity and metastasis of osteosarcoma in an animal model. 1856 75

Osteosarcoma is characterized by a high malignant and metastatic potential, which points to the need for new therapeutic strategies to prevent cell metastasis. In this study, we show that statin-induced HMG-CoA reductase inhibition reduces cell migration and invasion in human and murine osteosarcoma cells, independently of the genotype. The statin-induced reduction of cell migration and invasion was independent of induction of apoptosis and was geranylgeranylpyrophosphate-dependent. The statin reduced matrix metalloproteinase (MMP) 2, 9, and 14 and TIMP2 expression or activity in invading cells. Forced expression of MMP2 and MMP14 overcame the inhibitory effect of the statin on cell invasion, suggesting a role for these MMPs in invasive potential. We also investigated the mechanisms involved in the reduced MMP2 activity and cell invasion. Inhibition of JNK, but not ERK1/2 signaling, reduced MMP2 activity. Pharmacological or constitutive activation of JNK overcame the reduced MMP2 activity and cell invasion induced by the statin. The statin decreased JNK phosphorylation and c-Jun nuclear translocation, suggesting that HMG-CoA reductase inhibition targets the JNK-c-Jun signaling pathway. We showed that mevalonate or geranylgeranylpyrophosphate treatment prevented the statin-induced reduction in JNK phosphorylation, MMP2 activity, and cell invasion. Forced expression of a constitutively active form of RhoA increased JNK phosphorylation and overcame the inhibitory effect of atorvastatin on MMP2 activity and cell invasion. The data establish a link between RhoA, JNK, c-Jun, and MMP2 activity that is functionally involved in the reduction in osteosarcoma cell invasion by the statin. This suggests a novel strategy targeting RhoA-JNK-c-Jun signaling to reduce osteosarcoma cell tumorigenesis.
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PMID:Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion. 1875 69

Proteomics is a novel molecular profiling technology. It is mainly concerned with determining the structure, expression, localization, biochemical activity, interactions, and cellular roles of any proteins. Clinical research hopes to benefit from proteomics in the identification of new drug targets and the development of new diagnostic markers. Better to understand the mechanisms by which ascofuranone (AF), an isoprenoid antibiotic, regulates physiological or pathological events and induces responses in the pharmacological treatment of cancer, we performed differential analysis of the human osteosarcoma cells U2OS proteomes in response to this agent. The U2OS cell proteomes with and without treatment with AF were compared using two-dimensional electrophoresis, matrix-assisted laser desorption/ionization mass spectrometry, and bioinformatics. The largest differences in protein expression were observed for hydroxyindole O-methyltransferase, syntaxin-binding protein 1, the matrix metalloproteinase (MMP)-2, urokinase receptor, and endothelial protein C receptor. Changes in expression and activity of some selected proteins were confirmed by Western blotting, zymography, and reverse transcription-polymerase chain reaction analysis. In particular, we observed downregulated tumor growth related-proteins such as MMP-2 and endothelial protein C receptor. According to these results, AF might be useful as a potent chemotherapeutic agent.
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PMID:Proteome profiling of U2OS cell line in response to a prenylphenol antibiotic isolated from a phytopathogenic fungus. 1875 62


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