MicroRNA-503 suppresses cell proliferation and invasion in osteosarcoma via targeting insulin-like growth factor 1 receptor

Abstract

MicroRNAs (miRs) are a class of small non-coding RNAs and have key roles in various cancer types. Recently, miR-503 has been reported to act as a tumor suppressor in osteosarcoma. However, the detailed mechanism of the regulatory role of miR-503 in osteosarcoma cell proliferation and invasion has largely remained elusive. The present study found that miR-503 was significantly downregulated in osteosarcoma tissues compared to that in matched adjacent non-tumorous tissues. In addition, the expression of miR-503 in osteosarcoma of T3-T4 stage was significantly lower when compared with that in T1-T2 stage samples. miR-503 was also downregulated in osteosarcoma cell lines (Saos-2, MG63, U2OS and SW1353), when compared with that in the normal osteoblast cell line hFOB. Overexpression of miR-503 significantly inhibited the proliferation and invasion of U2OS cells and decreased the protein levels of insulin-like growth factor 1 receptor (IGF-1R), which was further identified as a novel target of miR-503 by a luciferase reporter assay. Moreover, overexpression of IGF-1R eliminated the suppressive effects of miR-503 on the proliferation and invasion of U2OS cells, suggesting that miR-503 inhibits osteosarcoma cell proliferation and invasion by directly targeting IGF-1R. Furthermore, IGF-1R was significantly upregulated in osteosarcoma tissues compared with that in adjacent non-tumor tissues, as well as in osteosarcoma cell lines compared with that in hFOB cells. In addition, the expression levels of IGF-1R were inversely correlated to the miR-503 levels in osteosarcoma tissues, suggesting that the increased IGF-1R expression may be caused by the reduced expression of miR-503. In conclusion, the present study demonstrated that miR-503 suppresses cell proliferation and invasion in osteosarcoma via targeting IGF-1R and thus highlights the importance of miR-503/IGF-1R signaling in the malignant progression of osteosarcoma.

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.…”

miR‐32 promotes esophageal squamous cell carcinoma metastasis by targeting CXXC5

“…MicroRNAs (miRNAs) have great potential to be useful biomarkers in cancer research. 14 miR-32 functioned as an antitumor miRNA, which has been shown to be downexpressed and to suppress some target genes to inhibit the malignant processes of lung cancer. [11][12][13] It is also common knowledge that abnormal miRNAs expression plays important regulatory roles in the occurrence and development of multiple cancers in which they maybe conduct as tumor suppressors or oncogenes by adjusting cell differentiation, proliferation, cell cycle, apoptosis, or metastasis.…”