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

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.

Cisplatin-resistant lung cancer cell–derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100–5p-dependent manner

“…27,28 Several researches proved that overexpression of miR-100 can sensitize cancer cells to DDP in various tumors. 23,29 Concurring with these studies, our research confirmed that the downregulated expression of miR-100-5p contributed to DDP resistance in lung cancer cells. The luciferase reporter in previous literatures 22,23 proved that mTOR is a direct target gene of miR-100-5p and can be regulated by directly binding to the 3′-UTR of mTOR.…”

“…23,29 Concurring with these studies, our research confirmed that the downregulated expression of miR-100-5p contributed to DDP resistance in lung cancer cells. The luciferase reporter in previous literatures 22,23 proved that mTOR is a direct target gene of miR-100-5p and can be regulated by directly binding to the 3′-UTR of mTOR. In our study, we did find that mTOR expression was negatively regulated by miR-100-5p, thereby modulating the sensitivity of lung cancer cells to DDP.…”

“…As shown in Figure 2D, the 3′-UTR of mTOR contains putative miR-100 complementary sites and the mirSVR score is -1.1698 and the PhastCons score is 0.6882. Besides, several studies 22,23 illuminated that miR-100-5p can regulate the expression of mTOR by directly binding to the 3′-UTR of mTOR by the luciferase reporter.…”

The Network of Non-coding RNAs in Cancer Drug Resistance

“…Deregulation of miR-100 has been reported in drug resistance; however, miR-100 expression can be either over-expressed or under-expressed in diverse cancers (134). In ovarian cancer, miR-100 targets mTOR therefore reverting the cell's chemoresistance toward cisplatin (135) and chondrosarcoma (136). In pancreatic cancer, miR-100 mimics inhibit proliferation and increase sensitivity to cisplatin by targeting FGFR3 (137).…”

Multiple Roles of MicroRNA-100 in Human Cancer and its Therapeutic Potential

“…For example, Li et al reported that transfection of lentivirual vector containing miR-100 mimics in pancreatic cancer cells could inhibit cancer cell proliferation and increase sensitivities to cisplatin through targeting FGFR3 [42]. Zhu et al also highlighted miR-100 as a tumor suppressor in chondrosarcoma and obtained evidence that overexpression of miR-100 could reverse the chemoresistance of cisplatin-resistant chondrosarcoma cells to cisplatin by directly targeting mTOR [74]. In addition, upregulated miR-100 with oncogenic potential in specific cancer types can be potential therapeutic targets for inhibition by using antisense oligonucleotides, sponges or locked nucleic acid (LNA) constructs [144][145][146].…”