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)

Methylation of promoter regions of CpG-rich sites is an important mechanism for silencing of tumor suppressor genes (TSG). To evaluate the role of tumor suppressor genes caspase-8 (CASP8), TIMP-3, E-cadherin (CDH1), p16INK4A, and MGMT in medulloblastoma tumorigenesis, 51 medulloblastomas (46 primary tumor specimens, 5 cell lines) were screened for methylation of promoter linked CpG-islands. For CASP8, we examined the 5' UTR region that has been shown to be associated with expression of CASP8. As detected by methylation specific PCR, methylation rate was low for TIMP-3 (3% of tumor samples; 1/5 cell lines), for MGMT (0% of tumor samples; 1/5 cell lines), for p16INK4A (2% of tumor samples; 2/5 cell lines) and for CDH1 (8% of tumor samples; 1/4 cell lines). CASP8, however, was methylated in 90% of tumor samples and 4/5 cell lines examined. Screening other tumor entities for CASP8 methylation, we found a similarly high level in 6 neuroblastoma cell lines in contrast to 5 osteosarcoma-, 4 Ewing's sarcoma- and 6 non-embryonic tumor cell lines without any increased promoter methylation. From our results we conclude that methylation of the CASP8 5' UTR region may play a role in inactivation of CASP8 in neural crest tumors.
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PMID:Promoter methylation pattern of caspase-8, P16INK4A, MGMT, TIMP-3, and E-cadherin in medulloblastoma. 1502 56

Connective tissue growth factor (CTGF) is a signaling molecule that primarily functions in extracellular matrix maintenance and repair. Increased Ctgf expression is associated with fibrosis in chronic organ injury. Studying the role of CTGF in fibrotic disease in vivo, however, has been hampered by perinatal lethality of the Ctgf null mice as well as the limited scope of previous mouse models of Ctgf overproduction. Here, we devised a new approach and engineered a single mutant mouse strain where the endogenous Ctgf-3' untranslated region (3'UTR) was replaced with a cassette containing two 3'UTR sequences arranged in tandem. The modified Ctgf allele uses a 3'UTR from the mouse FBJ osteosarcoma oncogene (c-Fos) and produces an unstable mRNA, resulting in 60% of normal Ctgf expression (Lo allele). Upon Cre-expression, excision of the c-Fos-3'UTR creates a transcript utilizing the more stable bovine growth hormone (bGH) 3'UTR, resulting in increased Ctgf expression (Hi allele). Using the Ctgf Lo and Hi mutants, and crosses to a Ctgf knockout or Cre-expressing mice, we have generated a series of strains with a 30-fold range of Ctgf expression. Mice with the lowest Ctgf expression, 30% of normal, appear healthy, while a global nine-fold overexpression of Ctgf causes abnormalities, including developmental delay and craniofacial defects, and embryonic death at E10-12. Overexpression of Ctgf by tamoxifen-inducible Cre in the postnatal life, on the other hand, is compatible with life. The Ctgf Lo-Hi mutant mice should prove useful in further understanding the function of CTGF in fibrotic diseases. Additionally, this method can be used for the production of mouse lines with quantitative variations in other genes, particularly with genes that are broadly expressed, have distinct functions in different tissues, or where altered gene expression is not compatible with normal development.
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PMID:A mouse strain where basal connective tissue growth factor gene expression can be switched from low to high. 2087 62

Osteosarcoma (OS) is the common histological form of primary bone cancer and one of the leading aggressive cancers in children under age fifteen. Although several genetic predisposing conditions have been associated with OS the understanding of its molecular etiology is limited. Here, we show that microRNAs (miRNAs) at the chr.14q32 locus are significantly downregulated in osteosarcoma compared to normal bone tissues. Bioinformatic predictions identified that a subset of 14q32 miRNAs (miR-382, miR-369-3p, miR-544 and miR-134) could potentially target cMYC transcript. The physical interaction between these 14q32 miRNAs and cMYC was validated using reporter assays. Further, restoring expression of these four 14q32 miRNAs decreased cMYC levels and induced apoptosis in Saos2 cells. We also show that exogenous expression of 14q32 miRNAs in Saos2 cells significantly downregulated miR-17-92, a transcriptional target of cMYC. The pro-apoptotic effect of 14q32 miRNAs in Saos2 cells was rescued either by overexpression of cMYC cDNA without the 3'UTR or with miR-17-92 cluster. Further, array comparative genomic hybridization studies showed no DNA copy number changes at 14q32 locus in OS patient samples suggesting that downregulation of 14q32 miRNAs are not due to deletion at this locus. Together, our data support a model where the deregulation of a network involving 14q32 miRNAs, cMYC and miR-17-92 miRNAs could contribute to osteosarcoma pathogenesis.
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PMID:Perturbation of 14q32 miRNAs-cMYC gene network in osteosarcoma. 2203 51

MicroRNAs are important gene regulators that play a profound role in tumorigenesis. MicroRNA-145 (miR-145), an important member in the family of microRNAs, is under-expressed in several types of tumors and acts as a tumor suppressor. The role and probable pathways of miR-145 in osteosarcoma carcinogenesis are still unknown. In this study, we found that miR-145 was significantly under-expressed in osteosarcoma tissues, and the over-expression of miR-145 could inhibit invasion and angiopoiesis of osteosarcoma cells. Furthermore, the results showed that vascular endothelial growth factor (VEGF) expression was down-regulated in osteosarcoma cells after miR-145 transfection. On the basis of these results, we performed the luciferase assay and verified that miR-145 could down-regulate VEGF at the translational level by partially binding to VEGF 3' untranslated region (3'UTR). Therefore, it can be concluded that miR-145 can inhibit invasion and metastasis of osteosarcoma cells. One of the mechanisms is the down-regulation of VEGF expression by miR-145 by binding to the 3'UTR of VEGF mRNA specifically. These novel findings may have extensive implications for an effective gene therapy of osteosarcoma.
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PMID:MicroRNA-145 targets vascular endothelial growth factor and inhibits invasion and metastasis of osteosarcoma cells. 2247 69

Recent studies have emphasized causative links between aberrant microRNA expression patterns and cancer progression. miR-183 is dysregulated in certain types of human cancers. The expression pattern, clinical significance, and biological role of miR-183 in osteosarcoma, however, remain largely undefined. In this paired analysis, we found that miR-183 was markedly down-regulated in osteosarcoma cells and tissues compared with matching normal bone tissues using RT-qPCR. Statistical analyses revealed that the expression levels of miR-183 significantly correlated with lung metastasis as well as with local recurrence of osteosarcoma. miR-183 expression was inversely correlated with Ezrin mRNA and protein expression levels in osteosarcoma cells as well as in a subset of primary osteosarcoma. Ectopically expressed miR-183 inhibited migratory and invasive abilities of osteosarcoma cells, whereas knockdown of endogenous miR-183 significantly enhanced these abilities. Using a luciferase reporter carrying the 3'-untranslated region (3'-UTR) of Ezrin, we identified Ezrin as a direct target of miR-183. Moreover, ectopic expression of Ezrin could significantly rescue miR-183-suppressed migration and invasion. Of interest, suppression of Ezrin by miR-183 caused a reduction of phosphorylated p44/42 (p-p44/42). Finally, suppression of Ezrin by RNAi mimicked miR-183 action in the suppression of migration and invasion, which was associated with down-regulation of p-p44/42. Taken together, these results suggest that as a tumor suppressor miRNA, miR-183 plays an important role in the aggressiveness of osteosarcoma.
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PMID:Down-regulation of miR-183 promotes migration and invasion of osteosarcoma by targeting Ezrin. 2252 61

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

Osteosarcoma (OS) is a primary bone tumor that is most prevalent during adolescence. RUNX2, which stimulates differentiation and suppresses proliferation of osteoblasts, is deregulated in OS. Here, we define pathological roles of RUNX2 in the etiology of OS and mechanisms by which RUNX2 expression is stimulated. RUNX2 is often highly expressed in human OS biopsies and cell lines. Small interference RNA-mediated depletion of RUNX2 inhibits growth of U2OS OS cells. RUNX2 levels are inversely linked to loss of p53 (which predisposes to OS) in distinct OS cell lines and osteoblasts. RUNX2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated RUNX2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated RUNX2 targeting microRNAs in human OS cells compared with mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated RUNX2 targeting microRNAs in OS. Exogenous supplementation of miR-34c markedly decreases RUNX2 protein levels, whereas 3'-UTR reporter assays establish RUNX2 as a direct target of miR-34c in OS cells. Importantly, Nutlin-3-mediated stabilization of p53 increases expression of miR-34c and decreases RUNX2. Thus, a novel p53-miR-34c-RUNX2 network controls cell growth of osseous cells and is compromised in OS.
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PMID:MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma. 2372 Jul 36

Recently, a group of microRNAs (miRNAs) were shown to be dysregulated in gliomas, and involved in glioma development. However, the effect of miRNA-miRNA functional networks on gliomas is poorly understood. In this study, we identified that FBJ murine osteosarcoma viral oncogene homolog (FOS)-mediated miR-181b/miR-21 signalling was critical for glioma progression. Using microarrays and quantitative RT-PCR (qRT-PCR), we found increased FOS in high grade gliomas. FOS depletion (via FOS-shRNA), inhibited invasion and promoted apoptosis in glioma cells. Using microarrays, combined with Pearson correlation analysis, we found FOS positively correlated with miR-21 expression. Reduction of FOS inhibited miR-21 expression by binding to the miR-21 promoter using luciferase reporter assays. Introduction of miR-21 abrogated FOS knockdown-induced cell invasion and apoptosis. Moreover, bioinformatics and luciferase reporter assays showed that miR-181b modulated FOS expression by directly targeting the binding site within the 3'UTR. Expression of FOS with a FOS cDNA lacking 3'UTR overrided miR-181b-induced miR-21 expression and cell function. Finally, immunohistochemistry (IHC) and in situ hybridisation (ISH) analysis revealed a significant correlation in miR-181b, FOS and miR-21 expression in nude mouse tumour xenograft and human glioma tissues. To our knowledge, it is the first time to demonstrate that miR-181b/FOS/miR-21 signalling plays a critical role in the progression of gliomas, providing important clues for understanding the key roles of transcription factor mediated miRNA-miRNA functional network in the regulation of gliomas.
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PMID:Involvement of FOS-mediated miR-181b/miR-21 signalling in the progression of malignant gliomas. 2381 Feb 50

Accumulating evidence has shown that microRNAs are involved in multiple processes in cancer development and progression. Recently, miR-335 has been identified as a tumor-suppressing microRNA in many human cancers. However, the specific function of miR-335 in osteosarcoma is unclear at this point. In this study, we found that the expression of miR-335 in osteosarcoma tissues and cell lines was much lower than that in normal control, respectively, and the downregulated miR-335 was significantly associated with lymph-node metastasis. Transfection of miR-335 mimics could significantly inhibit the cell migration and invasion in MG-63 and U2OS osteosarcoma cell lines. Moreover, we also showed that ROCK1 was negatively regulated by miR-335 at the posttranscriptional level, via a specific target site within the 3'UTR by luciferase reporter assay. The expression of ROCK1 was inversely correlated with miR-335 expression in osteosarcoma tissues, and knockdown of ROCK1 by siRNA-inhibited osteosarcoma cells migration and invasion resembling that of miR-335 overexpression. Thus, our findings suggest that miR-335 acts as tumor suppressor by targeting the ROCK1 gene and inhibiting osteosarcoma cells migration and invasion. The findings of this study contribute to current understanding of the functions of miR-335 in osteosarcoma.
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PMID:miR-335 suppresses migration and invasion by targeting ROCK1 in osteosarcoma cells. 2397 6

In this study, we investigated the roles of miR-132 in tumor growth of osteosarcoma. We found that overexpression of miR-132 significantly suppressed in vitro cell proliferation and in vivo tumor growth. In addition, miR-132 overexpression induced G1/S cell cycle arrest of osteosarcoma cells. Further study showed that miR-132 could interact with the 3'-untranslated region of cyclin E1 (CCNE1) gene and repress its expression. Re-expression of CCNE1 (without the 3'UTR) could partially abrogate the miR-132-induced cell proliferation inhibition. Of significance, contrary to CCNE1, expression level of miR-132 was significantly lower in osteosarcoma tissues than in the adjacent normal tissues. Taken together, these results indicate that miR-132 functions as a tumor suppressor in osteosarcoma and that its suppressive effects are mediated chiefly by repressing CCNE1 expression.
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PMID:miR-132 targeting cyclin E1 suppresses cell proliferation in osteosarcoma cells. 2444 7


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