Identification of LTF as a Prognostic Biomarker for Osteosarcoma.
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ABSTRACT:
SUBMITTER: Liu X
PROVIDER: S-EPMC8799371 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundOsteosarcoma (OS) is a type of primary malignant tumor, and increasing evidence shows the clinical benefits of immunotherapy in treating OS. However, the lack of comprehensive studies on the complex OS immune microenvironment hinders the application of immunotherapy. Thus, this study aimed to systematically explore the immune characteristics of OS and identify novel biomarkers for OS treatment.MethodsWe systematically studied the immune score and proportions of infiltrating immune cells in OS in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) databases using the ESTIMATE and CIBERSORT algorithms. Differential expression and functional analyses were used to identify dysregulated genes and explore their functions. Survival and Cox regression analyses were applied to establish an immune-related prognostic signature. Additionally, qPCR and immunohistochemistry were performed to validate the results.ResultsA total of 103 differentially expressed immune genes (DEIGs) were found in the TARGET-OS and GSE39058 databases, and these DEIGs were mainly enriched in leukocyte proliferation, leukocyte differentiation, osteoclast differentiation, natural killer (NK) cell-mediated cytotoxicity, and the adaptive immune system. A predictive signature was constructed based on the survival analysis, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.65. Moreover, we found that mitogen-activated protein kinase kinase kinase 15 (MAP3K15) can predict the prognosis of patients with OS and is closely related to CD4+ T cells and macrophages. The OS patients with high MAP3K15 expression had a significantly poorer prognosis.ConclusionsOur study found that MAP3K15, whose expression level is closely related to immune activity in tumors, is a critical immune-related biomarker, and our findings may provide a basis for OS immunotherapy.
| S-EPMC8350644 | biostudies-literature
Project description:Osteosarcoma often occurs in children and adolescents and causes poor prognosis. The role of RNA-binding proteins (RBPs) in malignant tumors has been elucidated in recent years. Our study aims to identify key RBPs in osteosarcoma that could be prognostic factors and treatment targets. GSE33382 dataset was downloaded from Gene Expression Omnibus (GEO) database. RBPs extraction and differential expression analysis was performed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to explore the biological function of differential expression RBPs. Moreover, we constructed Protein-protein interaction (PPI) network and obtained key modules. Key RBPs were identified by univariate Cox regression analysis and multiple stepwise Cox regression analysis combined with the clinical information from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. Risk score model was generated and validated by GSE16091 dataset. A total of 38 differential expression RBPs was identified. Go and KEGG results indicated these RBPs were significantly involved in ribosome biogenesis and mRNA surveillance pathway. COX regression analysis showed DDX24, DDX21, WARS and IGF2BP2 could be prognostic factors in osteosarcoma. Spearman's correlation analysis suggested that WARS might be important in osteosarcoma immune infiltration. In conclusion, DDX24, DDX21, WARS and IGF2BP2 might play key role in osteosarcoma, which could be therapuetic targets for osteosarcoma treatment.
| S-EPMC8120427 | biostudies-literature
Project description:MicroRNAs (miRNAs/miRs) are a class of small noncoding RNA molecules that have important roles in regulating the expression of target genes associated with the development and progression of cancer. The majority of miRNAs are expressed in a highly tissue- and region-specific manner, and released into the bloodstream as a consequences of different diseases. Furthermore, altered levels of miRNAs have been observed in several diseases, including cancer. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) demonstrated that circulating miR-17 levels were significantly upregulated in patients with osteosarcoma (OS) compared with healthy subjects. RT-qPCR also revealed that high levels of circulating miR-17 expression were inversely correlated with phosphatase and tensin homolog expression, which was identified as a target gene of miR-17 in OS tissues. Furthermore, the overall survival of patients with OS was shorter in those with high miR-17 expression compared with moderate and low expression. Taken together, these findings indicate that miR-17 may function as a useful diagnostic and prognosis biomarker or therapeutic target of OS.
| S-EPMC5228414 | biostudies-literature
Project description:Metastatic progression is the major cause of death in osteosarcoma, the most common bone malignancy in children and young adults. However, prognostic biomarkers and efficacious targeted treatments for metastatic disease remain lacking. Using an immunoproteomic approach, we discovered that autoantibodies against the cell-cycle kinase inhibitor p27 (KIP1, CDKN1B) were elevated in plasma of high-risk osteosarcoma patients. Using a large cohort of serum samples from osteosarcoma patients (n = 233), we validated that a higher level of the p27 autoantibody significantly correlated with poor overall and event-free survival (P < 0.05). Immunohistochemical analysis also showed that p27 was mislocalized to the cytoplasm in the majority of osteosarcoma cases and in highly metastatic osteosarcoma cell lines. We demonstrated that ectopic expression of cytoplasmic p27 promoted migration and invasion of osteosarcoma cells, whereas shRNA-mediated gene silencing suppressed these effects. In addition, mutations at the p27 phosphorylation sites S10 or T198, but not T157, abolished the migratory and invasive phenotypes. Furthermore, the development of pulmonary metastases increased in mice injected with cells expressing cytoplasmic p27 compared with an empty vector control. Collectively, our findings support further investigation of p27 as a potential prognostic biomarker and therapeutic target in osteosarcoma cases exhibiting aberrant p27 subcellular localization. Cancer Res; 76(13); 4002-11. ©2016 AACR.
| S-EPMC4930684 | biostudies-literature
Project description:BackgroundOver the past four decades, outcomes for osteosarcoma patients have plateaued as there have been few emerging therapies showing clinical results. Thus, the identification of novel biomarkers and therapeutic strategies are urgently needed to address these primary obstacles in patient care. Although the Myc-oncogene has known roles in oncogenesis and cancer cell growth, its expression and function in osteosarcoma are largely unknown.MethodsExpression of Myc was determined by Western blotting of osteosarcoma cell lines and patient tissues, and by immunohistochemistry of a unique osteosarcoma tissue microarray (TMA) constructed from 70 patient samples with extensive follow-up data. Myc specific siRNA and inhibitor 10058-F4 were applied to examine the effect of Myc inhibition on osteosarcoma cell proliferation. The clonogenicity and migration activity was determined by clonogenic and wound-healing assays. A mimic in vivo assay, three-dimensional (3D) cell culture model, was performed to further validate the effect of Myc inhibition on osteosarcoma cell tumorigenic markers.ResultsMyc was significantly overexpressed in human osteosarcoma cell lines compared with normal human osteoblasts, and also highly expressed in fresh osteosarcoma tissues. Higher Myc expression correlated significantly with metastasis and poor prognosis. Through the addition of Myc specific siRNA and inhibitor, we significantly reduced Myc protein expression, resulting in decreased osteosarcoma cell proliferation. Inhibition of Myc also suppressed the migration, clonogenicity, and spheroid growth of osteosarcoma cells.ConclusionOur results support Myc as an emerging prognostic biomarker and therapeutic target in osteosarcoma therapy.
| S-EPMC7222246 | biostudies-literature
Project description:BackgroundOsteosarcoma was the most common primary bone malignancy in children and adolescents. It was imperative to identify effective prognostic biomarkers for this cancer. This study was aimed to identify potential crucial genes of osteosarcoma by integrated bioinformatics analysis.MethodsIdentification of differentially expressed genes from public data gene expression profiles (GSE42352), functional and pathway enrichment analysis, protein-protein interaction (PPI) network construction and module analysis, Cox regression and survival analysis was conducted.ResultsTotally 17 co-differential genes were found to be differentially expressed. These genes were enriched in biological processes, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) pathway of inflammatory immune response. PPI network was constructed with 63 differentially expressed genes that co-existed between the test set and the validation set. The area under the receiver operating characteristic curve (AUC value) was 0.855, which indicated that the expression of PODN had a good diagnostic value for osteosarcoma. Furthermore, Cox regression and survival analysis revealed 5 genes were statistically significant.ConclusionsPODN was regarded as a potential biomarker for the diagnosis and prognosis of osteosarcoma, ACTA2, COL6A1, FAP, OLFML2B and COL6A3, can be used as potential prognostic indicators for osteosarcoma.
| S-EPMC8285818 | biostudies-literature
Project description:BackgroundCancer is a disease of abnormal cell proliferation caused by abnormal expression of cancer-related genes. However, it is still difficult to distinguish benign and malignant lesions in many cases. KIF4A has been reported to be associated with a variety of cancer lesions. We aimed to explore whether KIF4A could be used as a biomarker of pan-cancer diagnostic.MethodsWe identified twenty-eight cell cycle-related genes that were overexpressed in no less than ten types of cancer. We determined KIF4A mRNA and protein expression in osteosarcoma (OS) cells. Furthermore, to determine the effect of KIF4A in OS, we silenced KIF4A in OS cells and detected cell viability, colony formation, invasion, migration, apoptosis and cell cycle parameters.ResultsKIF4A exhibited upregulated expression in eleven types of cancer. Cell cycle-related genes are extensively overexpressed in various types of cancers. KIF4A overexpression can serve as a diagnostic and prognostic marker in various cancers. Silencing KIF4A inhibited the viability, colony formation, invasion and migration and induced apoptosis and cell cycle arrest of OS cells. Our findings revealed that high expression of KIF4A could serve as a diagnostic and prognostic marker in OS cancers.ConclusionKIF4A could serve as a pan-cancer diagnostic and prognostic marker. KIF4A could be used as a novel therapeutic target for OS.
| S-EPMC8142929 | biostudies-literature
Project description:Objective:Osteosarcoma is the most common primary bone tumor and most frequently develops during adolescence. PLOD family was mainly involved in lysyl hydroxylation and rarely investigated in cancers, especially in osteosarcoma. The aim of this study was to investigate the expression pattern and oncogenic role of PLODs in osteosarcoma. Methods:GEO datasets (GSE16088, GSE33382, and GSE16091) and validation cohort were used to analyze the expression pattern of PLODs in osteosarcoma. Kaplan-Meier survival analysis was used to explore the prognostic role of PLODs in patients with osteosarcoma. RNA interference of KRT19 was performed using small interfering RNA (siRNA) in MG-63 and U-2OS cells. The proliferation was detected using CCK8, clone formation assay, and EdU staining. Migration and invasion were determined using the transwell assay. Western blots and luciferase assays for ?-catenin-T-cell factor protein/?-catenin-lymphoid enhancer factor- (?-catenin-TCF/LEF-) driven transcriptional activity. Results:PLOD1 was upregulated in osteosarcoma tissues compared with control tissues both in public datasets and in in-house cohort. The expression of PLOD1 in osteosarcoma tissues was significantly associated with the status of distance metastasis and Enneking stage, while PLOD2 and PLOD3 expressed no difference between osteosarcoma and benign tissues and showed no correlation with tumor malignancy. Furthermore, Kaplan-Meier survival analysis revealed that patients with a higher level of PLOD1 had worse prognosis than those with a lower level of PLOD1. Downregulation of PLOD1 dramatically inhibited proliferation, migration, and invasion of MG-63 cells and U-2OS cells in vitro. Mechanistically, PLOD1 regulated ?-catenin signaling pathway in osteosarcoma. Conclusion:Our results indicated that PLOD1 promoted proliferation, migration, and invasion of osteosarcoma cells. PLOD1 was a novel prognostic marker, as well as a therapeutic target in osteosarcoma.
| S-EPMC7593720 | biostudies-literature
Project description:BACKGROUND:Prognostic biomarkers for osteosarcoma (OS) at the time of diagnosis are lacking. Necrotic response of OS to preoperative chemotherapy correlates with survival and is determined 3-4 months after diagnosis. The purpose of this study is to identify biomarkers that will stratify patients into good or poor responders to chemotherapy at diagnosis and determine the role of potential biomarkers in OS pathogenesis. PROCEDURE:Because OS may be caused by disruptions of osteogenic differentiation, and the Notch pathway is one regulator of bone development, we examined the link between Notch effectors, OS differentiation, and OS outcome. We probed the R2: Genomics Analysis and Visualization Platform for RNA expression levels of Notch targets in mixed high-grade OS pretreatment biopsies. We used human OS cell lines in vitro and in mice to determine the role of the Notch target hairy/enhancer of split 4 (Hes4) in OS. RESULTS:We found that in OS patients, high expression of Hes4 is correlated with decreased metastasis-free and overall survival. Human OS cells that overexpress Hes4 are more immature and have an increased invasive capacity in vitro. This was not universal to all Notch effectors, as Hes1 overexpression induced opposing effects. When injected into NSG mice, Hes4-overexpressing OS cells produced significantly larger, more lytic tumors and significantly more metastases than did control cells. CONCLUSIONS:Hes4 overexpression promotes a more aggressive tumor phenotype by preventing osteoblastic differentiation of OS cells. Hes4 expression may allow for the stratification of patients into good or poor responders to chemotherapy at diagnosis.
| S-EPMC6240354 | biostudies-literature
Project description:Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma.Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort.Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase.Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.
| S-EPMC5464875 | biostudies-other