Abstract
Exosomes are essential for several tumor progression-related processes, including the epithelial–mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) comprise a major group of exosomal components and regulate the neoplastic development of several cancer types; however, the progressive role of exosomal lncRNAs in bladder cancer have rarely been addressed. In this study, we identified two potential aggressiveness-promoting exosomal lncRNAs, LINC00960 and LINC02470. Exosomes derived from high-grade bladder cancer cells enhanced the viability, migration, invasion and clonogenicity of recipient low-grade bladder cancer cells and activated major EMT-upstream signaling pathways, including β-catenin signaling, Notch signaling, and Smad2/3 signaling pathways. Nevertheless, LINC00960 and LINC02470 were expressed at significantly higher levels in T24 and J82 cells and their secreted exosomes than in TSGH-8301 cells. Moreover, exosomes derived from LINC00960 knockdown or LINC02470 knockdown T24 cells significantly attenuated the ability of exosomes to promote cell aggressiveness and activate EMT-related signaling pathways in recipient TSGH-8301 cells. Our findings indicate that exosome-derived LINC00960 and LINC02470 from high-grade bladder cancer cells promote the malignant behaviors of recipient low-grade bladder cancer cells and induce EMT by upregulating β-catenin signaling, Notch signaling, and Smad2/3 signaling. Both lncRNAs may serve as potential liquid biomarkers for the prognostic surveillance of bladder cancer progression.
Highlights
Bladder cancer is the seventh most prevalent cancer worldwide and the second most common urological malignancy behind prostate cancer
Compared to the PBS control, T24-Conditioned media (ConMed) increased the migratory ability in the wound healing assay (Figure 1B,C). These results suggest that some component(s) in the conditioned media of higher-grade bladder cancer cells possess the ability to promote the migration of TSGH-8301 cells and that exosomes transmission should be competent for intercellular communication
TSGH-8301-Exos downregulated Smad2/3 and decreased their phosphorylation/activation. Both T24-Exos or J82-Exos induced epithelial to mesenchymal transition (EMT) in recipient TSGH-8301 cells, and three major upstream signaling cascades were obviously activated after T24-Exos or J82-Exos treatment. These results suggested that there were some broad-spectrum regulators in the exosomes derived from high-grade bladder cancer cells, which led to the comprehensive induction of the EMT process in recipient TSGH-8301 cells
Summary
Bladder cancer is the seventh most prevalent cancer worldwide and the second most common urological malignancy behind prostate cancer. In Taiwan, the incidence of bladder cancer is increasing annually [3]. Bladder cancer exhibits a high frequency of relapse and a poor clinical outcome once the tumors progress to muscle invasion and drug resistance [4,5,6,7,8]. Cells 2020, 9, 1419 of bladder cancer aggressiveness from low-grade to high-grade bladder cancer and the frequent progression to muscle-invasive bladder cancer. During epithelial to mesenchymal transition (EMT), epithelial cells are converted to migratory and invasive cells [9]. Loss of E-cadherin expression has long been considered to be a leading feature of EMT that leads to the loss of the typical polygonal, cobblestone morphology of epithelial cells
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