ABSTRACT
OBJECTIVE: Osteosarcoma is the most malignant and common primary bone tumor with a high rate of recurrence that mainly occurs in children and young adults. Therefore, it is vital to facilitate the development of novel effective therapeutic means and improve the overall prognosis of osteosarcoma patients via a deeper understanding of the mechanisms of chemoresistance in osteosarcoma progression. METHODS: In this research, the relationship between ITGB3 and the clinical characteristics of patients was detected through analysis of publicly available clinical datasets. The expression of ITGB3 was analysis in collected human osteosarcoma tissues. In addition, the potential functions of ITGB3 in the cisplatin resistance of osteosarcoma cells were investigated in vitro and in tumor xenotransplantation. Finally, the molecular mechanism of ITGB3 in the progression and recurrence of osteosarcoma were explored via transcriptome analysis. RESULTS: ITGB3 was identified as a potential regulator of tumorigenicity and cisplatin resistance in relapsed osteosarcoma. Furthermore, the decreased osteosarcoma cell proliferation and migration ability in ITGB3 knockout osteosarcoma cells were related to increased apoptosis and slowing cell cycle progression. In addition, ITGB3 had a positive correlation with cisplatin resistance in cells and tumor xenografts in mice. Accordingly, ITGB3 performed the functions of proliferation and cisplatin resistance in osteosarcoma through the MAPK and VEGF signaling pathways. CONCLUSION: Our results will contribute to a better understanding of the function and mechanism of ITGB3 in osteosarcoma cisplatin resistance and provide a novel therapeutic target to decrease cisplatin resistance and tumor recurrence in osteosarcoma patients.
Subject(s)
Antineoplastic Agents , Bone Neoplasms , Osteosarcoma , Child , Young Adult , Humans , Animals , Mice , Cisplatin/pharmacology , Cisplatin/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm/genetics , Apoptosis , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Osteosarcoma/drug therapy , Osteosarcoma/genetics , Osteosarcoma/metabolism , Bone Neoplasms/drug therapy , Bone Neoplasms/genetics , Bone Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation , Integrin beta3ABSTRACT
Osteosarcomas are prevalent in children and young adults and have a high recurrence rate. Cisplatin, doxorubicin, and methotrexate are common adjuvant chemotherapy drugs for treatment of osteosarcoma, but multidrug resistance is a growing problem. Therefore, understanding the molecular mechanisms of chemotherapy resistance in osteosarcoma cells is crucial for developing new therapeutic approaches and ultimately improving the prognosis of osteosarcoma patients. To identify genes associated with cisplatin resistance in osteosarcoma, we screened a large-scale mutant library generated by transfecting human osteosarcoma cells with a piggyBac (PB) transposon-based gene activation vector. Several candidate genes were identified by using Splinkerette-PCR paired with Next Generation Sequencing. We created a disease-free survival predictor model, which includes ZNF720, REEP3, CNNM2, and CGREF1, using TARGET (Therapeutically Applicable Research to Generate Effective Treatments) datasets. Additionally, the results of our enrichment analysis between the Four_genes_high group and Low_group suggested that these four genes may participate in cisplatin resistance in osteosarcoma through cross talk between various signaling pathways, especially the signaling pathway related to bone formation. These data may help guide future studies into chemotherapy for osteosarcoma.
