MicroRNA-302a inhibits osteosarcoma cell migration and invasion by directly targeting IGF-1R

Abstract

Osteosarcoma is one of the most frequent types of primary malignant bone neoplasm in children and adolescents. Despite advancements developed in therapeutic modalities, the 5-year overall survival rates for patients with metastatic osteosarcoma disease remain poor. The present study aimed to investigate the expression level of microRNA-302a (miR-302a) in osteosarcoma tissues and cell lines, and the biological roles of miR-302a in osteosarcoma cells. In addition, the molecular mechanism underlying its tumor suppressive roles was evaluated. miR-302a expression in osteosarcoma tissues and cell lines was detected using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Following transfection of miR-302a mimics or IGF-1R siRNA, transwell migration and invasion, luciferase reporter assay RT-qPCR and western blot assays were conducted in osteosarcoma cells. In the present study, the data demonstrated that miR-302a was frequently reduced in osteosarcoma tissue and cell lines. In addition, the expression of miR-302a was correlated with metastatic features of patients with osteosarcoma. Restoration of miR-302a expression significantly inhibited the migration and invasion capacity of osteosarcoma cells. Mechanistic studies indicated that insulin-like growth factor 1 receptor (IGF-1R) was a direct target gene of miR-302a. Overexpression of miR-302a resulted in decreased expression of IGF-1R at the mRNA and protein levels. Furthermore, the knockdown IGF-1R mimicked the functions of miR-302a overexpression on osteosarcoma cell migration and invasion. Collectively, the results of the current study indicate that miR-302a acts as a metastasis suppressing miRNA and could be investigated as a therapeutic target for the treatment of patients with osteosarcoma to prevent metastasis.

Targeting mutant TP53 as a potential therapeutic strategy for the treatment of osteosarcoma

“…We also explored the mechanisms underlining the anti‐tumor effects after targeting mutant TP53. The IGF‐1R signaling pathway plays a significant role in tumor proliferation, growth, and migration in osteosarcomas . Down regulation of IGF‐1R may be one aspect of the mechanism underlining the inhibition of proliferation, colony formation, and migration arising after targeting mutant TP53 in this study.…”

“…The IGF-1R signaling pathway plays a significant role in tumor proliferation, growth, and migration in osteosarcomas. 25,[35][36][37] Down regulation of IGF-1R may be one aspect of the mechanism underlining the inhibition of proliferation, colony formation, and migration arising after targeting mutant TP53 in this study. Indeed, it has been reported that down regulation of IGF-1R expression is associated with decreased proliferative activity in osteosarcoma cells.…”

“…In MDR osteosarcoma cells, inhibition of IGF‐1R by the inhibitor cyclolignan picropodophyllin, which is currently in clinical trials for cancer treatment, suppressed tumor proliferation, and induced apoptosis . Moreover, miR‐302a and miR‐503 have been shown to inhibit osteosarcoma cell migration and invasion by directly targeting IGF‐1R, which highlighted the significance of IGF‐1R in the regulation of cell migration in osteosarcomas . It is possible that there exists a positive relationship between mutant TP53 and the IGF‐1R signaling pathway, however the exact mechanisms remain unclear.…”

“…25 Moreover, miR-302a and miR-503 have been shown to inhibit osteosarcoma cell migration and invasion by directly targeting IGF-1R, which highlighted the significance of IGF-1R in the regulation of cell migration in osteosarcomas. 36,37 It is possible that there exists a positive relationship between mutant TP53 and the IGF-1R signaling pathway, however the exact mechanisms remain unclear. In this study, we have shown that targeting mutant TP53 downregulated IGF-1R in osteosarcoma cells in vitro.…”

Application of the microRNA‐302/367 cluster in cancer therapy

“…In specific BC cell lines, some scholars have found that vitamin C can reduce the reprogramming efficiency of the miR‐302/367 cluster by downregulating TET1 gene expression, which reverses the inhibition of cell invasion and proliferation by this cluster . Insulin‐like growth factor‐1R, can be directly targeted by miR‐302a, which plays a tumor suppressor role by inhibiting the invasion and migration of osteosarcoma cells . One recent study indicated that miR‐302‐3p can suppress cervical cancer metastasis through actions on its direct target, defective in DCUN1D1 .…”