ABSTRACT
Osteosarcoma is a highly metastatic, aggressive bone cancer that occurs in children and young adults worldwide. Circular RNAs (circRNAs) are crucial molecules for osteosarcoma progression. In this study, we aimed to investigate the impact of circMRPS35 overexpression and its interaction with FOXO1 via evaluating apoptosis, cell cycle, and bioinformatic analyses on the malignant development of osteosarcoma in MG63 and MNNG/HOS cells. We found that circMRPS35 overexpression reduced osteosarcoma cell viability and inhibited tumor growth in vivo. It increased the apoptosis rate and induced cell cycle arrest in osteosarcoma cells. We identified a potential interaction between circMRPS35 and FOXO1 with miR-105-5p using bioinformatics analysis. Overexpression of circMRPS35 decreased miR-105-5p expression, whereas miR-105-5p mimic treatment increased its expression. This mimic also suppressed the luciferase activity of circMRPS35 and FOXO1 and reduced FOXO1 expression. Overexpression of circMRPS35 elevated FOXO1 protein levels, but this effect was reversed by co-treatment with the miR-105-5p mimic. We demonstrated that inhibiting miR-105-5p decreased viability and induced apoptosis. Overexpression of FOXO1 or treatment with a miR-105-5p inhibitor could counteract the effects of circMRPS35 on viability and apoptosis in osteosarcoma cells. Therefore, we concluded that circMRPS35 suppressed the malignant progression of osteosarcoma via targeting the miR-105-5p/FOXO1 axis.
Subject(s)
Apoptosis , Bone Neoplasms , Forkhead Box Protein O1 , Gene Expression Regulation, Neoplastic , MicroRNAs , Osteosarcoma , RNA, Circular , Osteosarcoma/genetics , Osteosarcoma/metabolism , Osteosarcoma/pathology , RNA, Circular/genetics , RNA, Circular/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Forkhead Box Protein O1/metabolism , Forkhead Box Protein O1/genetics , Humans , Cell Line, Tumor , Animals , Bone Neoplasms/genetics , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Apoptosis/genetics , Mice , Disease Progression , Cell Proliferation/genetics , Mice, Nude , Cell Survival/geneticsABSTRACT
BACKGROUND: The standard treatment for localized osteosarcoma is neoadjuvant chemotherapy before surgery, followed by adjuvant chemotherapy. Our aim was to report the rate of histopathological response to neoadjuvant chemotherapy for the treatment of extremity osteosarcoma in Vietnam. METHODS: We performed a retrospective study of stage II conventional osteosarcoma patients under 40 years-old who received MAP regimen as neoadjuvant chemotherapy at the Vietnam National Cancer Hospital between June 2019 and June 2022. Histopathological response was evaluated using the Huvos grading system, in which a good histopathological response was defined as a necrotic rate of 90% or more. RESULTS: Thirty-five eligible patients were included in the study. Male patients accounted for 65.7%, with a median age of 16 years (range, 8-38 years). Of the 35 cases, 31 were reported as stage IIB (88.6%). The femur and tibia were the most common sites in our study, accounting for 51.4% and 34.3%, respectively. The most common pathologic subtype was osteoblastic osteosarcoma (68.6%), followed by chondroblastic subtype (20%). After two cycles of MAP-regimen neoadjuvant chemotherapy, 28 of 35 patients (80%) underwent limb-sparing surgery. A good histopathological response was observed in 18 of 35 patients (51.4%). There were significant correlations between the duration of symptoms (P = 0.016), LDH (P = 0.001) serum levels at initial presentation, and ALP (P = 0.043) serum levels at initial presentation with histopathological response. CONCLUSION: This retrospective study suggests a possible association between symptom duration, pre-treatment LDH levels, and pre-treatment ALP levels with histopathological response rates. Additional clinical investigations with long-term follow-up are needed to investigate survival outcomes in the Asian population.
Subject(s)
Bone Neoplasms , Neoadjuvant Therapy , Osteosarcoma , Humans , Osteosarcoma/drug therapy , Osteosarcoma/pathology , Osteosarcoma/therapy , Osteosarcoma/mortality , Male , Neoadjuvant Therapy/methods , Retrospective Studies , Adult , Adolescent , Vietnam , Young Adult , Female , Bone Neoplasms/pathology , Bone Neoplasms/drug therapy , Bone Neoplasms/therapy , Bone Neoplasms/mortality , Child , Chemotherapy, Adjuvant/methods , Chemotherapy, Adjuvant/statistics & numerical data , Neoplasm Staging , Extremities/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds whole genome sequencing and reverse-phase protein array profiling data, which can be correlated with drug testing results. In addition, four additional osteosarcoma models are described for use in the research community.
Subject(s)
Bone Neoplasms , Osteosarcoma , Xenograft Model Antitumor Assays , Osteosarcoma/genetics , Osteosarcoma/pathology , Humans , Animals , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Mice , Whole Genome Sequencing/methods , Protein Array Analysis/methods , Transcriptome , Disease Models, AnimalSubject(s)
Cyclooxygenase 2 , Neoplastic Stem Cells , Osteosarcoma , Osteosarcoma/genetics , Osteosarcoma/pathology , Animals , Dogs , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/metabolism , Cyclooxygenase 2/genetics , Cyclooxygenase 2/metabolism , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Bone Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Dog Diseases/genetics , Gene Expression ProfilingABSTRACT
BACKGROUND: Osteosarcoma (OS) is a malignant bone tumor that commonly occurs in children and adolescents under the age of 20. Dysregulation of microRNAs (miRNAs) is an important factor in the occurrence and progression of OS. MicroRNA miR-744-5p is aberrantly expressed in various tumors. However, its roles and molecular targets in OS remain unclear. METHODS: Differentially expressed miRNAs in OS were analyzed using the Gene Expression Omnibus dataset GSE65071, and the potential hub miRNA was identified through weighted gene co-expression network analysis. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of miR-744-5p in OS cell lines. In vitro experiments, including CCK-8 assays, colony formation assays, flow cytometry apoptosis assays, and tube formation assays, were performed to explore the effects of miR-744-5p on OS cell biological behaviors. The downstream target genes of miR-744-5p were predicted through bioinformatics, and the binding sites were validated by a dual-luciferase reporter assay. RESULTS: The lowly expressed miRNA, miR-744-5p, was identified as a hub miRNA involved in OS progression through bioinformatic analysis. Nuclear factor I X (NFIX) was confirmed as a direct target for miR-744-5p in OS. In vitro studies revealed that overexpression of miR-744-5p could restrain the growth of OS cells, whereas miR-744-5p inhibition showed the opposite effect. It was also observed that treatment with the conditioned medium from miR-744-5p-overexpressed OS cells led to poorer proliferation and angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, NFIX overexpression restored the suppression effects of miR-744-5p overexpression on OS cell growth and HUVECs angiogenesis. CONCLUSION: Our results indicated that miR-744-5p is a potential tumor-suppressive miRNA in OS progression by targeting NFIX to restrain the growth of OS cells and angiogenesis in HUVECs.
Subject(s)
Bone Neoplasms , Cell Proliferation , MicroRNAs , NFI Transcription Factors , Neovascularization, Pathologic , Osteosarcoma , Humans , Apoptosis/genetics , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , MicroRNAs/metabolism , Neovascularization, Pathologic/genetics , NFI Transcription Factors/genetics , NFI Transcription Factors/metabolism , Osteosarcoma/genetics , Osteosarcoma/pathologyABSTRACT
Accumulating evidence has demonstrated that F-box protein 22 (FBXO22) participates in tumour development and progression in various types of human malignancies. However, the functions and detailed molecular mechanisms of FBXO22 in osteosarcoma tumorigenesis and progression remain elusive. In this study, we aimed to determine the effects of FBXO22 on the cell proliferation, migration and invasion of osteosarcoma cells using cell counting kit-8 and Matrigel Transwell approaches. Moreover, we explored the molecular mechanisms by which FBXO22 mediated oncogenesis and progression in osteosarcoma via Western blotting, immunoprecipitation and ubiquitination. We found that FBXO22 depletion inhibited the proliferation, migration and invasion of osteosarcoma cells, whereas FBXO22 overexpression increased the proliferation and motility of osteosarcoma cells. Mechanistically, FBXO22 promoted the ubiquitination and degradation of FoxO1 in osteosarcoma cells. FBXO22 depletion reduced cell proliferation and motility via regulation of FoxO1. Taken together, our findings provide new insight into FBXO22-induced osteosarcoma tumorigenesis. The inhibition of FBXO22 could be a promising strategy for the treatment of osteosarcoma.
Subject(s)
Cell Movement , Cell Proliferation , F-Box Proteins , Forkhead Box Protein O1 , Gene Expression Regulation, Neoplastic , Osteosarcoma , Ubiquitination , Osteosarcoma/metabolism , Osteosarcoma/pathology , Osteosarcoma/genetics , Humans , Forkhead Box Protein O1/metabolism , Forkhead Box Protein O1/genetics , F-Box Proteins/metabolism , F-Box Proteins/genetics , Cell Movement/genetics , Cell Line, Tumor , Proteolysis , Disease Progression , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Bone Neoplasms/genetics , Neoplasm Invasiveness , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinogenesis/pathology , Receptors, Cytoplasmic and NuclearABSTRACT
BACKGROUND: Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Despite more intensive chemotherapy regimens and improved local control therapy, there is still a considerable rate of recurrent/progressive disease. METHODS: A retrospective study of 50 relapsed/progressive ES patients who were treated at the National Cancer Institute (NCI), Cairo University, during the period from 1st of January 2008 to the end of December 2018, to assess different prognostic variables and disease outcomes. RESULTS: Out of fifty eligible cases, 32 patients (64%) had disease recurrence, and 18 (36%) developed disease progression on treatment. The median follow-up period was 7.4 months. The median overall survival (OS) was 7.5 months, and the cumulative OS was 64% at 6 months and 32.6% at 1 year. The cumulative event-free survival (EFS) was 41.3% at 6 months and 22.3% at 1 year. Patients with disease recurrence had better OS and EFS than patients with disease progression (p = 0.019). Patients who underwent local control at relapse/progression had a significantly better outcome than patients who received chemotherapy only (p < 0.001). Recurrence > 2 years from initial diagnosis was the only independent predictor of better survival outcome. CONCLUSIONS: Patients with relapsing/progressive ES portended a poor outcome, with disease progression on treatment faring worse than relapse. Better outcome was observed in patients who experienced recurrence > 2 years after diagnosis, patients with disease recurrence rather than disease progression on treatment, and patients who underwent local control along with intensive chemotherapy.
Subject(s)
Bone Neoplasms , Disease Progression , Neoplasm Recurrence, Local , Sarcoma, Ewing , Humans , Sarcoma, Ewing/mortality , Sarcoma, Ewing/therapy , Sarcoma, Ewing/pathology , Sarcoma, Ewing/drug therapy , Sarcoma, Ewing/diagnosis , Female , Male , Child , Adolescent , Prognosis , Neoplasm Recurrence, Local/pathology , Bone Neoplasms/mortality , Bone Neoplasms/drug therapy , Bone Neoplasms/pathology , Bone Neoplasms/therapy , Retrospective Studies , Child, Preschool , Treatment Outcome , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Egypt/epidemiologyABSTRACT
Juvenile ossifying fibroma (JOF) is an uncommon benign fibro-osseous lesion (BFOL) of the maxillofacial bones with a locally aggressive nature and a high recurrence rate. Murine Double Minute 2 (MDM2) is an oncogene located at chromosome 12 (12q13-15) that inhibits the tumor suppressor gene TP53. The presence of MDM2 gene locus amplification is a useful molecular adjunct in the evaluation of some sarcomas, including low-grade intramedullary osteosarcoma (LGIOS). JOF and LGIOS have some overlapping clinical and histopathological features. The aim of this study is to evaluate a series of JOF for the presence of MDM2 gene locus amplification using fluorescence in-situ hybridization (FISH). MATERIALS AND METHODS: With IRB approval, a search of the institutional files of the archives of the Oral Pathology and Surgical Pathology biopsy services at the University of Florida Health was performed. The cases were re-evaluated by an oral pathology resident, an oral and maxillofacial pathologist, and a bone and soft tissue pathologist. Cases with consensus in diagnosis were selected (n = 9) for MDM2 testing. Testing by FISH for MDM2 gene locus amplification was applied to all retrieved cases. RESULTS: The examined cases were all negative for MDM2 gene locus amplification via FISH testing. CONCLUSION: In our small series, JOF did not demonstrate MDM2 gene locus abnormality, a characteristic of LGIOS. This finding suggests that JOF has a distinct underlying pathogenesis. If confirmed in a larger series, these findings may be useful in distinguishing these two entities in cases with overlapping features or when minimal biopsy material is available.
Subject(s)
Fibroma, Ossifying , Gene Amplification , In Situ Hybridization, Fluorescence , Proto-Oncogene Proteins c-mdm2 , Humans , Proto-Oncogene Proteins c-mdm2/genetics , Fibroma, Ossifying/genetics , Fibroma, Ossifying/pathology , Male , Female , Adolescent , Child , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Child, Preschool , Young AdultABSTRACT
BACKGROUND: Bone radiation-induced sarcomas (B-RIS) are secondary neoplasms with reportedly worse overall survival than de novo bone sarcoma. Treatment strategy for these neoplasms remains uncertain. Our systematic review sought to assess overall survival based on histology and surgical intervention. METHODS: A systemic review was conducted following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines and registered in PROSPERO (438415). Studies describing oncologic outcomes of patients with B-RIS in the appendicular and axial skeleton were included. The Strengthening the Reporting of Observational Studies in Epidemiology checklist was used for quality assessment. Survival analysis by histologic subtype and surgery type was performed in a subset of 234 patients from 11 articles with individualized data. A total of 20 articles with a total of 566 patients were included. The most frequent location was the pelvis (27.7%), and the main histological types were osteosarcoma (69.4%), undifferentiated pleomorphic sarcoma (14.1%), and fibrosarcoma (9.2%). Limb-salvage and amputation were performed in 68.5% and 31.5% of cases, respectively. RESULTS: Local recurrence was 13%, without difference between limb-salvage surgery and amputation (p = 0.51). The metastasis rate was 42.3%. Five-year OS was 43.7% (95% confidence interval [CI], 33.3%-53.5%) for osteosarcoma, 31.5% (95% CI, 11.3%-54.2%) for UPS, and 28.1% (95% CI, 10.6%-48.8%) for fibrosarcoma. Five-year OS was 49.2% (95% CI, 35.3%-61.6%) for limb-salvage and 46.9% (95% CI, 29.1%-62.9%) for amputation. There was no difference in 5-year OS between histologic subtypes (p = 0.18) or treatment type (p = 0.86). CONCLUSION: B-RIS demonstrated poor OS at 5 years after initial management regardless of histology. Limb-salvage surgery was not associated with lower 5-year OS compared with amputation. Future studies should compare both groups while controlling for confounders. LEVEL OF EVIDENCE: Level III. See Instructions for Authors for a complete description of levels of evidence.
Subject(s)
Bone Neoplasms , Neoplasms, Radiation-Induced , Sarcoma , Humans , Bone Neoplasms/radiotherapy , Bone Neoplasms/surgery , Bone Neoplasms/mortality , Bone Neoplasms/pathology , Sarcoma/radiotherapy , Sarcoma/pathology , Sarcoma/surgery , Sarcoma/mortality , Neoplasms, Radiation-Induced/pathology , Neoplasms, Radiation-Induced/surgery , Neoplasms, Radiation-Induced/etiology , Limb Salvage , Male , Female , Osteosarcoma/pathology , Osteosarcoma/mortality , Osteosarcoma/surgery , Osteosarcoma/radiotherapy , Adult , Treatment Outcome , Middle Aged , AdolescentABSTRACT
PURPOSE: To investigate the clinical and pathological features of osteochondroma in maxillofacial region, and to summarize the clinicopathological features of rare osteochondroma malignant transformation in order to provide clinical guidance. METHODS: From January 2018 to September 2023, a total of 171 patients with osteochondroma were retrospectively collected in Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Their preoperative CT and clinicopathological features were analyzed. RESULTS: Of the 171 patients with osteochondroma in maxillofacial bone, 66%ï¼113/171ï¼ were females and 34% were male. Their age ranged from 11-76 with an average age was 44 years old. Of the 171 cases, 95.3%ï¼163/171ï¼in mandible condyle, 4%(7/171) in mandible processus coronoideus, and 0.5%ï¼1/171ï¼ in zygomatic arch. The imaging findings showed that the thickness of cartilaginous cap was less than 1 cm in 98%ï¼159/161ï¼ cases with condyle lesions. Only 2 cases(2/171, 1.1%) had malignant transformation. One was diagnosed with secondary chondrosarcoma, another developed low-grade osteosarcoma. CONCLUSIONS: Osteochondroma in maxillofacial region mostly occurs in females, and most commonly located in condylar process, with a malignant change rate of 1.1%, which is similar to that of other parts of the body. Imaging findings have important guiding significance for the diagnosis of osteochondroma malignant change.
Subject(s)
Cell Transformation, Neoplastic , Osteochondroma , Humans , Osteochondroma/pathology , Female , Male , Adult , Middle Aged , Adolescent , Retrospective Studies , Child , Aged , Tomography, X-Ray Computed , Mandibular Neoplasms/pathology , Mandibular Neoplasms/diagnostic imaging , Young Adult , Osteosarcoma/pathology , Bone Neoplasms/pathology , Mandibular Condyle/pathology , Chondrosarcoma/pathology , Zygoma/pathologyABSTRACT
Liquid-liquid phase separation (LLPS) facilitates the formation of membraneless organelles within cells, with implications in various biological processes and disease states. AT-rich interactive domain-containing protein 1A (ARID1A) is a chromatin remodeling factor frequently associated with cancer mutations, yet its functional mechanism remains largely unknown. Here, we find that ARID1A harbors a prion-like domain (PrLD), which facilitates the formation of liquid condensates through PrLD-mediated LLPS. The nuclear condensates formed by ARID1A LLPS are significantly elevated in Ewing's sarcoma patient specimen. Disruption of ARID1A LLPS results in diminished proliferative and invasive abilities in Ewing's sarcoma cells. Through genome-wide chromatin structure and transcription profiling, we identify that the ARID1A condensate localizes to EWS/FLI1 target enhancers and induces long-range chromatin architectural changes by forming functional chromatin remodeling hubs at oncogenic target genes. Collectively, our findings demonstrate that ARID1A promotes oncogenic potential through PrLD-mediated LLPS, offering a potential therapeutic approach for treating Ewing's sarcoma.
Subject(s)
Chromatin Assembly and Disassembly , DNA-Binding Proteins , RNA-Binding Protein EWS , Sarcoma, Ewing , Transcription Factors , Humans , Sarcoma, Ewing/genetics , Sarcoma, Ewing/metabolism , Sarcoma, Ewing/pathology , Transcription Factors/metabolism , Transcription Factors/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Cell Line, Tumor , RNA-Binding Protein EWS/metabolism , RNA-Binding Protein EWS/genetics , Gene Expression Regulation, Neoplastic , Cell Proliferation , Oncogene Proteins, Fusion/metabolism , Oncogene Proteins, Fusion/genetics , Proto-Oncogene Protein c-fli-1/metabolism , Proto-Oncogene Protein c-fli-1/genetics , Chromatin/metabolism , Carcinogenesis/genetics , Animals , Mice , Protein Domains , Bone Neoplasms/genetics , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Phase SeparationABSTRACT
WNT signaling regulates osteosarcoma proliferation. However, there is controversy in the field of osteosarcoma as to whether WNT signaling is pro- or anti-tumorigenic. WNT-targeting therapeutics, both activators and inhibitors, are compared. WNT5B, a ß-catenin-independent ligand, and WNT10B, a ß-catenin-dependent WNT ligand, are each expressed in osteosarcomas, but they are not expressed in the same tumors. Furthermore, WNT10B and WNT5B regulate different histological subtypes of osteosarcomas. Using WNT signaling modulators as therapeutics may depend on the WNT ligand and/or the activated signaling pathway.
Subject(s)
Bone Neoplasms , Osteosarcoma , Wnt Proteins , Wnt Signaling Pathway , Osteosarcoma/metabolism , Osteosarcoma/pathology , Osteosarcoma/drug therapy , Humans , Wnt Proteins/metabolism , Wnt Proteins/antagonists & inhibitors , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Bone Neoplasms/drug therapy , Wnt Signaling Pathway/drug effects , Animals , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins/genetics , Molecular Targeted Therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , beta Catenin/metabolism , Gene Expression Regulation, NeoplasticABSTRACT
PURPOSE: Prognostic factors have been well described for osteosarcoma, but analyses evaluating the further course of long-term survivors are lacking. We used the large database of the Cooperative Osteosarcoma Study Group (COSS) to perform such an analysis. PATIENTS AND METHODS: The COSS database 1980-04/2019 was searched for 5-year survivors of primary high-grade central osteosarcoma of the extremities or trunk. Identified patients were analyzed for their further survival outcomes, assessing potentially prognostic and predictive factors already evident at initial disease presentation and treatment as well as their disease course during the first 5 years of follow-up. RESULTS: Two thousand and nine former eligible patients were identified (median age at initial diagnosis 15.1 (2.5-63.0) years; male vs. female 1149 (57.2%) vs. 860 (42.8%); extremities vs. trunk 1927 (95.9%) vs. 82 (4.1%); extremity primaries <1/3 vs. ≥1/3 of the involved bone 997 (67.8%) vs. 474 (32.2%) (456 unknown); localized vs. primary metastatic 1881 (93.6%) vs. 128 (6.4%); osteosarcoma as a secondary malignancy 41/2009 (2.0%)). Therapy starting by chemotherapy versus primary surgery 1860 (92.6%) versus 149 (7.4%); definitive tumor surgery by limb salvage versus ablative 1347 (67.0%) versus 659 (1 no surgery, 2 unknown); tumor response to preoperative chemotherapy documented for 1765 (94.9%) patients receiving neoadjuvant chemotherapy, good (<10% viable tumor) versus poor 1130 (64.0%) versus 635 (36.0%), local radiotherapy documented for 19 (0.9%) tumors. Recurrence during preceding 5 years no versus yes 1681 (83.7%) versus 328 (16.3%). Median follow-up starting 5 years after initial diagnosis 6.1 (0.002-32.2) years; 1815 survivors and 194 deaths. Overall survival after another 5/10/15/20 years 91.7%/88.9%/85.8%/83.4% for all patients; 97.5%/95.2%/92.4%/89.9% if in remission years 1-5 versus 62.7%/57.3%/53.0%/51.2% if recurrence year 1-5 (p < 0.001). Significant predictors of survival for all patients age at diagnosis (p = 0.038), tumor site (p = 0.030), having experienced the osteosarcoma as secondary malignancy (p < 0.001), tumor response to preoperative chemotherapy (p = 0.002). Multivariate Cox regression testing possible for 1759 (87.6%) patients with complete dataset: Having had a recurrence in years 1-5 (p < 0.001), older age at diagnosis (p = 0.009), and osteosarcoma as secondary malignancy (p = 0.013) retained significance. DISCUSSION: Highly important predictors of death such as the extent of tumor response to chemotherapy no longer remain valid after 5-year survival. The individual history of malignancies and their outcomes seems to gain pivotal importance. CONCLUSION: This benchmark analysis clearly defined risk factors for the further course of 5-year survivors from osteosarcoma. It argues for large disease-oriented databases as well as for very long follow-up periods. Novel findings will most likely require innovative statistical models to analyze such cohorts.
Subject(s)
Bone Neoplasms , Osteosarcoma , Humans , Osteosarcoma/mortality , Osteosarcoma/therapy , Osteosarcoma/pathology , Male , Female , Adult , Middle Aged , Adolescent , Child , Bone Neoplasms/mortality , Bone Neoplasms/therapy , Bone Neoplasms/pathology , Young Adult , Child, Preschool , Prognosis , Extremities/pathology , Cancer Survivors/statistics & numerical dataABSTRACT
Objective: To analyze the clinicopathological features of prostate cancers with BRCA2 pathogenic mutations, and the association between BRCA2 pathogenic mutation and clinicopathological characteristics. Patient survivals were also examined. Methods: Clinicopathological data of 249 prostate cancer patients who underwent genetic testing in West China Hospital of Sichuan University, Chengdu, China from June 2014 to August 2021 were collected. A retrospective analysis of histopathological morphology, clinicopathological characteristics, and patient survivals was conducted. Results: The genetic testing in the 249 prostate cancer patients showed a pathogenic mutation of DNA damage repair gene (DRG) in 73 cases (73/249, 29.3%), including 22 cases (8.8%) with BRCA2 pathogenic mutation and 51 cases with pathogenic mutations of other DRG. Among the 22 patients with BRCA2 pathogenic mutation, 14 patients (5.6%) harbored germline mutations and 8 patients (3.2%) somatic mutations. Their ages ranged from 48 to 91 years, with a median of 67 years. Seventeen patients (77.3%) had distant metastasis, including 16 cases with bone metastasis and 1 case with multiple metastases. Thirteen patients (59.1%) were castration-resistant prostate cancer. The histological type was mainly classical prostatic acinar adenocarcinoma, including 16 cases (72.7%) with intraductal carcinoma of the prostate (IDC-P). Six cases (27.3%) showed focal neuroendocrine differentiation. Perineural/vascular invasion and extraprostatic extension were seen in 11 cases (50.0%) and 8 cases (36.4%), respectively. The Gleason scores of 19 patients (86.4%) were≥8. IDC-P was more commonly found in patients with BRCA2 germline pathogenic mutation than those with BRCA2 somatic pathogenic mutation, other DRG pathogenic mutation or no-DRG pathogenic mutation (P=0.002). With a total follow-up time of 189 months, the median overall survival (OS) was 132.3 months. Patients with DRG pathogenic mutation had shorter OS than those with no-DRG pathogenic mutation (P=0.040). The OS of patients with BRCA2 germline pathogenic mutation did not significantly differ from that of patients with BRCA2 somatic pathogenic mutation, other DRG pathogenic mutation or no-DRG pathogenic mutation (P=0.216). Conclusions: The presence of BRCA2 gene pathogenic mutation is common in the prostate cancers with high Gleason grade, advanced clinical stage, and castration resistance. IDC-P is more commonly noted in cases with BRCA2 germline pathogenic mutation than those without. Patients with DRG pathogenic mutation have shorter OS than those with no-DRG pathogenic mutation, but there is no significant association between BRCA2 pathogenic mutations and OS.
Subject(s)
BRCA2 Protein , Mutation , Prostatic Neoplasms , Humans , Male , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , BRCA2 Protein/genetics , Aged , Retrospective Studies , Middle Aged , Prognosis , Aged, 80 and over , Bone Neoplasms/genetics , Bone Neoplasms/secondary , Bone Neoplasms/pathologySubject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Gene Rearrangement , Perivascular Epithelioid Cell Neoplasms , Humans , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Perivascular Epithelioid Cell Neoplasms/genetics , Perivascular Epithelioid Cell Neoplasms/pathology , Perivascular Epithelioid Cell Neoplasms/metabolism , Male , Adult , Middle Aged , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Bone Neoplasms/metabolism , Diagnosis, Differential , In Situ Hybridization, Fluorescence , ImmunohistochemistryABSTRACT
Osteosarcoma (OS) is an aggressive and highly lethal bone tumor, highlighting the urgent need for further exploration of its underlying mechanisms. In this study, we conducted analyses utilizing bulk transcriptome sequencing data of OS and healthy control samples, as well as single cell sequencing data, obtained from public databases. Initially, we evaluated the differential expression of four tumor microenvironment (TME)-related gene sets between tumor and control groups. Subsequently, unsupervised clustering analysis of tumor tissues identified two significantly distinct clusters. We calculated the differential scores of the four TME-related gene sets for Clusters 1 (C1) and 2 (C2), using Gene Set Variation Analysis (GSVA, followed by single-variable Cox analysis. For the two clusters, we performed survival analysis, examined disparities in clinical-pathological distribution, analyzed immune cell infiltration and immune evasion prediction, assessed differences in immune infiltration abundance, and evaluated drug sensitivity. Differentially expressed genes (DEGs) between the two clusters were subjected to Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA). We conducted Weighted Gene Co-expression Network Analysis (WGCNA) on the TARGET-OS dataset to identify key genes, followed by GO enrichment analysis. Using LASSO and multiple regression analysis we conducted a prognostic model comprising eleven genes (ALOX5AP, CD37, BIN2, C3AR1, HCLS1, ACSL5, CD209, FCGR2A, CORO1A, CD74, CD163) demonstrating favorable diagnostic efficacy and prognostic potential in both training and validation cohorts. Using the model, we conducted further immune, drug sensitivity and enrichment analysis. We performed dimensionality reduction and annotation of cell subpopulations in single cell sequencing analysis, with expression profiles of relevant genes in each subpopulation analyzed. We further substantiated the role of ACSL5 in OS through a variety of wet lab experiments. Our study provides new insights and theoretical foundations for the prognosis, treatment, and drug development for OS patients.
Subject(s)
Biomarkers, Tumor , Bone Neoplasms , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Osteosarcoma , Single-Cell Analysis , Transcriptome , Tumor Microenvironment , Humans , Osteosarcoma/genetics , Osteosarcoma/immunology , Osteosarcoma/mortality , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Bone Neoplasms/genetics , Bone Neoplasms/immunology , Bone Neoplasms/mortality , Bone Neoplasms/pathology , Biomarkers, Tumor/genetics , Prognosis , Male , Female , Gene Regulatory NetworksABSTRACT
BACKGROUND: Osteosarcoma is a soft tissue neoplasm with elevated recurrence risk and highly metastatic potential. Metal response element binding transcriptional factor 2 (MTF2) has been revealed to exert multiple activities in human tissues. The present research was conducted to explore the functions and related response mechanism of MTF2 in osteosarcoma which have not been introduced yet. METHODS: Bioinformatics tools identified the differential MTF2 expression in osteosarcoma tissues. MTF2 expression in osteosarcoma cells was examined with Western blot. Cell Counting Kit-8 (CCK-8) assay, 5-Ethynyl-2'-deoxyuridine (EDU) staining, wound healing as well as transwell assays measured cell proliferation, migration and invasion, respectively. Flow cytometry assay detected the cellular apoptotic level. Western blot also measured the expressions of proteins associated with epithelial mesenchymal transition (EMT), apoptosis and enhancer of zeste homolog 2 (EZH2)/secreted frizzled-related protein 1 (SFRP1)/Wnt signaling. Co-immunoprecipitation (Co-IP) assay confirmed MTF2-EZH2 interaction. RESULTS: MTF2 expression was increased in osteosarcoma tissues and cells. MTF2 interference effectively inhibited the proliferation, migration and invasion of osteosarcoma cells and promoted the cellular apoptotic rate. MTF2 directly bound to EZH2 and MTF2 silence reduced EZH2 expression, activated SFRP1 expression and blocked Wnt signaling in osteosarcoma cells. EZH2 upregulation or SFRP1 antagonist WAY-316606 partly counteracted the impacts of MTF2 down-regulation on the SFRP1/Wnt signaling and the biological phenotypes of osteosarcoma cells. CONCLUSIONS: MTF2 might down-regulate SFRP1 to activate Wnt signaling and drive the progression of osteosarcoma via interaction with EZH2 protein.
Subject(s)
Bone Neoplasms , Cell Proliferation , Enhancer of Zeste Homolog 2 Protein , Osteosarcoma , Wnt Signaling Pathway , Osteosarcoma/metabolism , Osteosarcoma/pathology , Osteosarcoma/genetics , Humans , Enhancer of Zeste Homolog 2 Protein/metabolism , Enhancer of Zeste Homolog 2 Protein/genetics , Wnt Signaling Pathway/physiology , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Bone Neoplasms/genetics , Cell Proliferation/physiology , Cell Line, Tumor , Intercellular Signaling Peptides and Proteins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Apoptosis/physiology , Transcription Factors/metabolism , Transcription Factors/genetics , Membrane Proteins/metabolism , Membrane Proteins/genetics , Cell Movement/physiology , Disease Progression , Gene Expression Regulation, NeoplasticABSTRACT
BACKGROUND: Integrin-Binding Sialoprotein (IBSP) has been implicated in tumor progression across various cancers. However, the specific role of IBSP in breast cancer remains underexplored. There is a need to investigate the mechanisms by which IBSP influences breast cancer progression and its potential as a therapeutic target. AIMS: This study aims to elucidate the role of IBSP in breast cancer, particularly its impact on tumor progression and its relationship with prognosis. We also seek to understand the underlying mechanisms, including the involvement of the BMP-SMAD signaling pathway, and to explore the potential of targeting IBSP for therapeutic interventions. METHODS AND RESULTS: Overexpression of IBSP in breast cancer cells led to increased migration and invasion, whereas IBSP interference reduced these behaviors, indicating its role in enhancing tumor progression. Differentially expressed genes were significantly enriched in the BMP-SMAD signaling pathway, a critical pathway for osteogenic differentiation. Transcription Factor Binding: Dual luciferase reporter assays demonstrated that SMAD4 specifically binds to the IBSP promoter, establishing a regulatory link between SMAD4 and IBSP expression. Silencing IBSP (si-IBSP) mitigated the effects of SMAD4-induced tumor proliferation, confirming that IBSP acts as a downstream target of SMAD4 in the BMP signaling pathway. CONCLUSION: Our study reveals that IBSP plays a significant role in breast cancer progression through the BMP-SMAD4 signaling pathway. Targeting IBSP could be a promising therapeutic strategy for breast cancer treatment. Further research into IBSP inhibitors may offer new avenues for improving treatment outcomes and managing breast cancer more effectively.
Subject(s)
Bone Neoplasms , Breast Neoplasms , Cell Proliferation , Integrin-Binding Sialoprotein , Signal Transduction , Smad4 Protein , Humans , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/genetics , Female , Bone Neoplasms/secondary , Bone Neoplasms/pathology , Bone Neoplasms/metabolism , Bone Neoplasms/genetics , Smad4 Protein/metabolism , Smad4 Protein/genetics , Integrin-Binding Sialoprotein/metabolism , Integrin-Binding Sialoprotein/genetics , Mice , Animals , Bone Morphogenetic Proteins/metabolism , Gene Expression Regulation, Neoplastic , Cell Movement , Cell Line, Tumor , Prognosis , Mice, NudeABSTRACT
BACKGROUND: Chondrosarcoma (CHS), a bone malignancy, poses a significant challenge due to its heterogeneous nature and resistance to conventional treatments. There is a clear need for advanced prognostic instruments that can integrate multiple prognostic factors to deliver personalized survival predictions for individual patients. This study aimed to develop a novel prediction tool based on recursive partitioning analysis (RPA) to improve the estimation of overall survival for patients with CHS. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed, including demographic, clinical, and treatment details of patients diagnosed between 2000 and 2018. Using C5.0 algorithm, decision trees were created to predict survival probabilities at 12, 24, 60, and 120 months. The performance of the models was assessed through confusion scatter plot, accuracy rate, receiver operator characteristic (ROC) curve, and area under ROC curve (AUC). RESULTS: The study identified tumor histology, surgery, age, visceral (brain/liver/lung) metastasis, chemotherapy, tumor grade, and sex as critical predictors. Decision trees revealed distinct patterns for survival prediction at each time point. The models showed high accuracy (82.40%-89.09% in training group, and 82.16%-88.74% in test group) and discriminatory power (AUC: 0.806-0.894 in training group, and 0.808-0.882 in test group) in both training and testing datasets. An interactive web-based shiny APP (URL: https://yangxg1209.shinyapps.io/chondrosarcoma_survival_prediction/) was developed, simplifying the survival prediction process for clinicians. CONCLUSIONS: This study successfully employed RPA to develop a user-friendly tool for personalized survival predictions in CHS. The decision tree models demonstrated robust predictive capabilities, with the interactive application facilitating clinical decision-making. Future prospective studies are recommended to validate these findings and further refine the predictive model.