miRNA-100 Inhibits Human Bladder Urothelial Carcinogenesis by Directly Targeting mTOR

Abstract

miRNAs are involved in cancer development and progression, acting as tumor suppressors or oncogenes. In this study, miRNA profiling was conducted on 10 paired bladder cancer tissues using 20 GeneChip miRNA Array, and 10 differentially expressed miRNAs were identified in bladder cancer and adjacent noncancerous tissues of any disease stage/grade. After being validated on expanded cohort of 67 paired bladder cancer tissues and 10 human bladder cancer cell lines by quantitative real-time PCR (qRT-PCR), it was found that miR-100 was downregulated most significantly in cancer tissues. Ectopic restoration of miR-100 expression in bladder cancer cells suppressed cell proliferation and motility, induced cell-cycle arrest in vitro, and inhibited tumorigenesis in vivo both in subcutaneous and in intravesical passage. Bioinformatic analysis showed that the mTOR gene was a direct target of miR-100. siRNA-mediated mTOR knockdown phenocopied the effect of miR-100 in bladder cancer cell lines. In addition, the cancerous metastatic nude mouse model established on the basis of primary bladder cancer cell lines suggested that miR-100/mTOR regulated cell motility and was associated with tumor metastasis. Both mTOR and p70S6K (downstream messenger) presented higher expression levels in distant metastatic foci such as in liver and kidney metastases than in primary tumor. Taken together, miR-100 may act as a tumor suppressor in bladder cancer, and reintroduction of this mature miRNA into tumor tissue may prove to be a therapeutic strategy by reducing the expression of target genes. Mol Cancer Ther; 12(2); 207–19. ©2012 AACR.

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

“…MiR-100 has been shown its tumorsuppressor functions in several cancers including ovarian cancer (Nagaraja et al, 2010), bladder cancer (Xu et al, 2013), hepatocellular carcinoma (Chen et al, 2013), cutaneous squamous cell carcinoma (Henson et al, 2009) and lung cancer (Liu et al, 2012). A recent miRNA array analysis described that miR-100 was down regulated in chondrosarcoma cells, indicating miR-100 might act as a tumor suppressor in human chondrosarcoma (Yoshitaka et al, 2013).…”

“…Hundreds of miRNAs have been well-studied to regulate gene expression and play essential roles in a variety of biological processes including proliferation, differentiation, migration, cell cycle, and apoptosis (Croce et al, 2009;Ameres et al, 2013). It has been reported that miRNAs are involved in drug resistance (Zheng et al, 2010), and acting as potential oncogenes or tumor suppressors (Ma et al, 2010;Xu et al, 2013). MiR-100 has been reported play a tumor suppressor role through multiple pathways.…”

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

“…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.…”

Prognostic role of microRNA-100 in patients with bladder cancer

“…Their study demonstrated the effects of miR-100 on cell growth rates and clonogenicity capacity in the 5637 cell line, emphasizing a possible effect of this miRNA on bladder carcinoma pathogenesis. Xu et al (2013) found that the mTOR gene was a direct target of miR-100. siRNA-mediated mTOR knockdown phenocopied the effect of miR-100 in bladder cancer cell lines.…”

“…Both mTOR and p70S6K (downstream messenger) presented higher expression levels in distant metastatic foci such as in liver and kidney metastases than in the primary tumor. Taken together, miR-100 may act as a tumor suppressor in bladder cancer, and reintroduction of this mature miRNA into tumor tissue may prove to be a therapeutic strategy by reducing the expression of target genes (Xu et al, 2013). However, the clinical significance and prognostic value of miR-100 in bladder cancer have not been investigated.…”