MicroRNA-100 Resensitizes Resistant Chondrosarcoma Cells to Cisplatin through Direct Targeting of mTOR

Zhe Zhu,Yin-Feng Zhang,Lin Nie,Cun-Ping Wang

doi:10.7314/apjcp.2014.15.2.917

Zhe Zhu, Yin-Feng Zhang + Show 2 more

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https://doi.org/10.7314/apjcp.2014.15.2.917

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Abstract

Chondrosarcomas are malignant cartilage-forming tumors of bone which exhibit resistance to both chemotherapy and radiation treatment. miRNAs have been well demonstrated to regulate gene expression and play essential roles in a variety of biological processes, including proliferation, differentiation, migration, cell cycling and apoptosis. In this study, we obtained evidence that miR-100 acts as a tumor suppressor in human chondrosarcomas. Interestingly, cisplatin resistant chondrosarcoma cells exhibit decreased expression of miR-100 compared with parental cells. In addition, we identified mTOR as a direct target of miR-100. Overexpression of miR-100 complementary pairs to the 3' untranslated region (UTR) of mTOR, resulted in sensitization of cisplatin resistant cells to cisplatin. Moreover, recovery of the mTOR pathway by overexpression of S6K desensitized the chondrosarcoma cells to cisplatin, suggesting the miR-100-mediated sensitization to cisplatin dependent on inhibition of mTOR. In summary, the present studies highlight miR-100 as a tumor suppressor in chondrosarcoma contributing to anti-chemoresistance. Overexpression of miR-100 might be exploited as a therapeutic strategy along with cisplatin-based combined chemotherapy for the treatment of clinical chondrosarcoma patients.

Highlights

Chondrosarcoma is the second most frequent primary malignant type of primary bone malignancy after osteosarcoma (Fiorenza et al, 2002)
Since miR-100 has been studied to act as a tumor suppressor in multiple tumor types, we first examined the expression of miR-100 in human chondrosarcoma cells and normal chondrocyte cell
MiR-100 was significantly down regulated in multiple chondrosarcoma cell lines compared with normal chondrocyte cell (Figure 1A), suggesting miR-100 might be a tumor suppressor in human chondrosarcoma

Summary

Introduction

Chondrosarcoma is the second most frequent primary malignant type of primary bone malignancy after osteosarcoma (Fiorenza et al, 2002). We performed luciferase reporter analysis by co-transfecting a vector containing pMIR reporter-luciferase fused with original sequence or predicted binding site mutant of the 3’-UTR of mTOR mRNA and pre-miR-100 or control microRNA. Overexpression of miR-100 decreased the luciferase activity of the reporter with wild type 3’-UTR of mTOR by about 60% in CH-2879 cells (Figure 3C).

Results

Conclusion