RESUMEN
Currently, chemotherapeutic drugs are widely used for the treatment of osteosarcoma. However, many of these drugs exhibit shortcomings such as poor efficacy, high toxicity, and tolerance. Isoquercitrin (ISO) is a traditional Chinese medicine that has been proved to exert good therapeutic effects on various tumors; however, its role in osteosarcoma has not been reported. Here, we observed that ISO exerted a marked inhibitory effect on the occurrence and development of osteosarcoma in a time- and dose-dependent manner. First, we determined that ISO significantly inhibited proliferation, induced EMT-related migration and invasion and induced apoptosis of osteosarcoma cells in vitro. Concurrently, we also observed that both ß-catenin and its downstream genes (c-Myc, CyclinD1, and Survivin) were significantly down-regulated. To verify if the anti-tumor effect of ISO was related to the Wnt/ß-catenin signaling pathway, we altered the protein expression level of ß-catenin using recombinant lentivirus, then we observed that the effects of ISO on the proliferation, metastasis, and apoptosis of osteosarcoma cells were significantly reversed. Additionally, we used a nude mouse xenograft model and observed that ISO significantly inhibited the growth of osteosarcoma and improved the survival rate of the animal models. In conclusion, this study demonstrates that ISO can exert anti-tumor effects in part by inhibiting the Wnt/ß-catenin signaling pathway, thus providing a new potential therapeutic strategy for the treatment of osteosarcoma.
RESUMEN
Background: Several studies have reported that circRNAs have a crucial function in the tumorigenesis of various cancers. However, the expression and function of circOMA1 in osteosarcoma is unknown. Methods: circOMA1 was identified through bioinformatics analysis. qRT-PCR was used to assess the expressions of circOMA1, miR-1294, and c-Myc in osteosarcoma tissues. Further, we performed functional experiments to explore the biological function of circOMA1 in osteosarcoma. Moreover, a luciferase reporter assay, RNA immunoprecipitation (RIP), and fluorescence in situ hybridisation (FISH) assay were performed to demonstrate the association between circOMA1 and miR-1294. Results: circOMA1 exhibited considerable upregulation in osteosarcoma tissues compared with adjacent normal tissues. Silencing circOMA1 suppressed osteosarcoma progression in vitro and in vivo. Mechanically, circOMA1 functioned as a sponge of miR-1294 to upregulate c-Myc expression. Conclusion: circOMA1 played the role of an oncogene in osteosarcoma and promoted osteosarcoma progression by mediating the miR-1294/c-Myc pathway, which might be a new target for treating osteosarcoma.
RESUMEN
Osteosarcoma is the most common malignant bone tumor, and although there has been significant progress in its management, metastases often herald incurable disease. Here we defined genes differentially expressed between primary and metastatic osteosarcoma as metastasis-related genes (MRGs) and used them to construct a novel six-MRG prognostic signature for overall survival of patients with osteosarcoma. Validation in internal and external datasets confirmed satisfactory accuracy and generalizability of the prognostic model, and a nomogram based on the signature and clinical variables was constructed to aid clinical decision-making. Of the six MRGs, FHIT is a well-documented tumor suppressor gene that is poorly defined in osteosarcoma. Consistent with tumor suppressor function, FHIT was downregulated in osteosarcoma cells and human osteosarcoma samples. FHIT overexpression inhibited osteosarcoma proliferation, migration, and invasion both in vitro and in vivo. Mechanistically, FHIT overexpression upregulate the epithelial marker E-cadherin while repressing the mesenchymal markers N-cadherin and vimentin. Our six-MRG signature represents a novel and clinically useful prognostic biomarker for patients with osteosarcoma, and FHIT might represent a therapeutic target by reversing epithelial to mesenchymal transition.