RESUMO
OBJECTIVE: Osteosarcoma is a rare primary malignant tumor of the bone characterized by poor survival rates, owing to its unclear pathogenesis. Rho GTPase-activating protein 44 (ARHGAP44), which belongs to the Rho GTPase-activating protein family, has promising applications in the targeted therapy of tumors. Therefore, this study aimed to investigate the biological function of ARHGAP44 in osteosarcoma and its possible application as a therapeutic target. METHODS: The expression level of ARHGAP44 in osteosarcoma and its relationship with tumor prognosis were detected using Gene Expression Omnibus database analysis and immunohistochemical staining of clinical specimens. The cell model of ARHGAP44 knockdown was constructed, and the effects of this gene on the malignant biological behavior of osteosarcoma cells were investigated using CCK-8, clone formation, transwell invasion, wound healing, and flow cytometry assays. Western blotting was performed to detect the expression of ARHGAP44, p53, C-myc, and Cyclin D1 in osteosarcoma. RESULTS: Biogenic analysis showed that ARHGAP44 was highly expressed in osteosarcoma. This result was associated with poor tumor prognosis and negatively correlated with the expression of the tumor suppressor gene p53. Immunohistochemistry and western blotting revealed significantly upregulated expression of ARHGAP44 in osteosarcoma tissues. Additionally, Kaplan-Meier analysis of clinical specimens suggested that ARHGAP44 was negatively correlated with tumor prognosis. CCK-8, clone formation, transwell invasion, wound healing, and flow cytometry assays showed that downregulation of ARHGAP44 expression significantly reduced the malignant biological behavior of osteosarcoma cells. Furthermore, western blotting showed that the expression level of p53 in osteosarcoma cells was significantly increased after the downregulation of ARHGAP44 expression, whereas the expression of C-myc and Cyclin D1 was significantly decreased compared with that in the control group. CONCLUSION: ARHGAP44 was highly expressed in osteosarcoma and was negatively correlated with its prognosis. The downregulation of ARHGAP44 expression reduced the malignant biological behavior of osteosarcoma cells. These findings suggest that the downregulation of ARHGAP44 expression inhibits the malignant progression of osteosarcoma by regulating the p53/C-myc/Cyclin D1 pathway, demonstrating the potential of ARHGAP44 as a therapeutic target for osteosarcoma.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Apoptose , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/patologia , Sincalida/genética , Sincalida/metabolismo , Sincalida/farmacologia , Proteína Supressora de Tumor p53/genéticaRESUMO
The dysregulation of alternative splicing (AS) is frequently found in cancer and considered as key markers for cancer progression and therapy. Transformer 2 (TRA2), a nuclear RNA binding protein, consists of transformer 2 alpha homolog (TRA2A) and transformer 2 beta homolog (TRA2B), and plays a role in the regulation of pre-mRNA splicing. Growing evidence has been provided that TRA2A and TRA2B are dysregulated in several types of tumors, and participate in the regulation of proliferation, migration, invasion, and chemotherapy resistance in cancer cells through alteration of AS of cancer-related genes. In this review, we highlight the role of TRA2 in tumorigenesis and metastasis, and discuss potential molecular mechanisms how TRA2 influences tumorigenesis and metastasis via controlling AS of pre-mRNA. We propose that TRA2Ais a novel biomarker and therapeutic target for cancer progression and therapy.
