Mechanism Of Osteosarcoma Metastasis Research Articles

Hypoxia inducible factor-1ɑ as a potential therapeutic target for osteosarcoma metastasis.

Osteosarcoma (OS) is a malignant tumor originating from mesenchymal tissue. Pulmonary metastasis is usually present upon initial diagnosis, and metastasis is the primary factor affecting the poor prognosis of patients with OS. Current research shows that the ability to regulate the cellular microenvironment is essential for preventing the distant metastasis of OS, and anoxic microenvironments are important features of solid tumors. During hypoxia, hypoxia-inducible factor-1α (HIF-1α) expression levels and stability increase. Increased HIF-1α promotes tumor vascular remodeling, epithelial-mesenchymal transformation (EMT), and OS cells invasiveness; this leads to distant metastasis of OS cells. HIF-1α plays an essential role in the mechanisms of OS metastasis. In order to develop precise prognostic indicators and potential therapeutic targets for OS treatment, this review examines the molecular mechanisms of HIF-1α in the distant metastasis of OS cells; the signal transduction pathways mediated by HIF-1α are also discussed.

Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma.

Osteosarcoma (OS) is the most common type of primary malignant bone tumor. The early lung metastasis of osteosarcoma is one of the main factors of poor prognosis. Therefore, searching for new targets and new mechanisms of osteosarcoma metastasis is essential for the prevention and treatment of osteosarcoma. Our previous studies suggested that fatty acid synthase (FASN) was an oncogene and promoted osteosarcoma. In addition, it is reported that the expression of miR-195 was negatively correlated with osteosarcoma. Aberrant DNA methylation can reversely regulate the expression of miRNAs. However, whether miR-195 could target FASN in osteosarcoma and whether ectopic DNA methylation is the upstream regulatory mechanism of miR-195 in metastasis of osteosarcoma are not fully studied. The expressions were detected by qPCR and western blot, and methylation level was determined by methylation-specific PCR. Luciferase reporter assay, MTT, wound healing, and Transwell assay were used. We found that the expression of miR-195 was low in osteosarcoma. The methylation of miR-195 was high. miR-195 targeted and decreased the expression of FASN. In osteosarcoma, miR-195 inhibited cell proliferation, cell migration, and invasion. The methylation of miR-195 was related to decreased miR-195, it might promote osteosarcoma.

LncRNA LOC100129620 promotes osteosarcoma progression through regulating CDK6 expression, tumor angiogenesis, and macrophage polarization.

Osteosarcoma is a malignant tumor with high mortality in children and adolescents. The mechanism of osteosarcoma metastasis is currently unclear. Abnormal expression of long non-coding RNA (lncRNA) plays an important role in tumor metastasis. We used bioinformatics to analyze the differences in gene expression between osteosarcoma in situ and osteosarcoma lung metastases. CCK-8 was used to detect the effect of lncRNA LOC100129620 on the proliferation of osteosarcoma cells. The effect of LOC100129620 on the invasion of osteosarcoma cells was assessed by Transwell assay. The regulatory effect of LOC100129620 on miR-335-3p was examined using RNA pull-down and luciferase reporter gene assays. The effect of LOC100129620 on the polarization of macrophages was detected by quantitative real-time fluorescent PCR. The results show that LOC100129620 can promote the proliferation and migration of osteosarcoma cells. LOC100129620 can promote the proliferation of osteosarcoma in vivo. LOC100129620 can bind to miR-335-3p and regulate its function. MiR-335-3p mediates the regulatory effects of LOC100129620 on CDK6. LOC100129620 promotes the formation of blood vessels and the polarization of macrophages. The LOC100129620/miR-335-3p/CDK6 signaling pathway promotes the metastasis of osteosarcoma by regulating the proliferation of osteosarcoma cells, angiogenesis, and macrophage polarization.

MiR-4295 promotes cell proliferation, migration and invasion of osteosarcoma through targeting interferon regulatory factor 1.

Osteosarcoma (OS) is the most common form of primary malignant bone tumor. Despite encouraging progress in the treatment of OS, the survival rate for patients with OS has remained unchanged over the past 40 years. It has been established that miRNA plays a crucial regulatory role in the progression and development of OS. To explore the potential association of miRNAs with OS, bioinformatics techniques were used to screen for differentially expressed miRNA genes in OS in the Gene Expression Omnibus database. In the GSE70367 database, it was revealed that miR-4295 expression was abnormally elevated in the expression of OS cells. To characterize the potential function of miR-4295 in OS, the expression levels of miR-4295 in 30 samples of OS and adjacent normal tissues was examined. The results revealed that the expression of miR-4295 was significantly increased in OS tissues compared with the paired normal tissues. Moreover, the expression levels of miR-4295 in OS cell lines (MG-63 and Saos-2) were significantly higher compared with those in the normal human mesenchymal stem cells. In addition, miR-4295 was associated with OS cell proliferation, migration and invasion. Furthermore, it was demonstrated that the expression of interferon regulatory factor (IRF)1, a tumor suppressor, was regulated by miR-4295 directly in OS cells. Taken together, the present results revealed that miR-4295 may act as a tumor activator by targeting IRF1 during the progression of OS. Investigating miR-4295 may provide novel insight into the mechanisms of OS metastasis, and inhibition and targeting miR-4295 may be a novel therapeutic strategy for the treatment of OS.

A risk score model for the prediction of osteosarcoma metastasis.

Osteosarcoma is the most common primary solid malignancy of the bone, and its high mortality usually correlates with early metastasis. In this study, we developed a risk score model to help predict metastasis at the time of diagnosis. We downloaded and mined four expression profile datasets associated with osteosarcoma metastasis from the Gene Expression Omnibus. After data normalization, we performed LASSO logistic regression analysis together with 10‐fold cross validation using the GSE21257 dataset. A combination of eight genes (RAB1,CLEC3B,FCGBP,RNASE3,MDL1,ALOX5AP,VMO1 and ALPK3) were identified as being associated with osteosarcoma metastasis. These genes were put into a gene risk score model, and the prediction efficiency of the model was then validated using three independent datasets (GSE33383, GSE66673, and GSE49003) by plotting receiver operating characteristic curves. The expression levels of the eight genes in all datasets were shown as heatmaps, and gene ontology gene annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. These eight genes play a role in cancer‐related biological processes, such as apoptosis and biosynthetic processes. Our results may aid in elucidating the possible mechanisms of osteosarcoma metastasis, and may help to facilitate the individual management of patients with osteosarcoma after treatment.

A support vector machine and a random forest classifier indicates a 15-miRNA set related to osteosarcoma recurrence.

BackgroundOsteosarcoma, which originates in the mesenchymal tissue, is the prevalent primary solid malignancy of the bone. It is of great importance to explore the mechanisms of metastasis and recurrence, which are two primary reasons accounting for the high death rate in osteosarcoma.Data and methodsThree miRNA expression profiles related to osteosarcoma were downloaded from GEO DataSets. Differentially expressed miRNAs (DEmiRs) were screened using MetaDE.ES of the MetaDE package. A support vector machine (SVM) classifier was constructed using optimal miRNAs, and its prediction efficiency for recurrence was detected in independent datasets. Finally, a co-expression network was constructed based on the DEmiRs and their target genes.ResultsIn total, 78 significantly DEmiRs were screened. The SVM classifier constructed by 15 miRNAs could accurately classify 58 samples in 65 samples (89.2%) in the GSE39040 database, which was validated in another two databases, GSE39052 (84.62%, 22/26) and GSE79181 (91.3%, 21/23). Cox regression showed that four miRNAs, including hsa-miR-10b, hsa-miR-1227, hsa-miR-146b-3p, and hsa-miR-873, significantly correlated with tumor recurrence time. There were 137, 147, 145, and 77 target genes of the above four miRNAs, respectively, which were assigned to 17 gene ontology functionally annotated terms and 14 Kyoto Encyclopedia of Genes and Genomes pathways. Among them, the “Osteoclast differentiation” pathway contained a total of seven target genes and was analyzed further.ConclusionThe 15-miRNAs-based SVM classifier provides a potential useful tool to predict the recurrence of osteosarcoma. Our results suggest the possible mechanisms of osteosarcoma metastasis and recurrence and provide fresh DEmiRs as potential biomarkers or therapeutic targets for osteosarcoma.

Decrease in stathmin expression by arsenic trioxide inhibits the proliferation and invasion of osteosarcoma cells via the MAPK signal pathway.

Osteosarcoma (OS) is the most common type of malignant bone tumor in children and adolescents. In total, 40–50% of patients with OS experience metastasis, and thus have a poor prognosis. Our previous study demonstrated that arsenic trioxide (As2O3) combined with doxorubicin [also known as Adriamycin (ADM)] significantly inhibited OS cell proliferation by downregulating stathmin expression. The present study investigated the effect and mechanism of stathmin expression on OS cell invasion. It was identified that the expression of stathmin was increased in human ADM-resistant OS MG63 (MG63/dox) cells compared with the level in the normal osteoblast hFoB1.19cell line using western blot analysis. Lentiviral-mediated small hairpin RNA (shRNA) was constructed to silence stathmin expression of MG63/dox cells. In transwell assay, stathmin-knockdown significantly suppressed migration and invasion in MG63/dox cells. As2O3 combined with ADM inhibited the migration and invasion of MG63/dox cells, and was associated with the downregulation of phosphorylated-mitogen-activated protein kinase (MAPK) 1 and β-catenin, and upregulation of phosphorylated-MAPK8 and E-cadherin. In addition, stathmin-knockdown significantly suppressed tumor growth and increased E-cadherin expression in a xenograft nude mouse model. Taken together, these data suggested that As2O3 combined with ADM inhibited stathmin-mediated invasion via the MAPK pathway. Elucidation of the mechanism for stathmin downregulation by As2O3 may provide novel insights into the mechanism of OS metastasis.

Establishment and analysis of osteosarcoma cell sublines with different metastatic characteristics.

The aim of this study is to establish human osteosarcoma MG-63 cell sublines with different metastatic characteristics and provide good experimental models for mechanism study of osteosarcoma metastasis. Six cell sublines were screened and established by using the in vitro cloning technology. In vitro invasion experiments, cellular electrophoretic mobility determinations, cellular proliferation rate determinations, and soft agar clone formation assays were used to compare, analyze, and identify the metastatic characteristics of various cell sublines. The results indicated that the invasion capacity, cellular electrophoretic mobility, cell proliferation, and soft agar clone formation capacity of A2, A3, and A16 sublines were higher than those of A1, A6, and A20 sublines. There was no significant difference in various values determined among A2, A3, and A16, and among A1, A6, and A20 (P > 0.05), but there were significant differences in various values determined between the former three and the latter three (P < 0.05). In conclusion, MG-63 cell sublines with different metastatic characteristics can be established by combining several technologies and can contribute to further research on the mechanism of osteosarcoma metastasis.

Molecular and cellular mechanisms of osteosarcoma metastasis: current knowledge and perspectives

Metastasis remains the main cause of death in cancer patients, and current treatment options are insufficient. There is a great need to define new strategies. The process of metastasis is regulated by specific sets of metastasis genes. Whereas some metastasis genes may be common for all cancers, som