Abstract
Objective: To investigate the regulatory function of exosome-transmitted miR-128 and chemokine (C-C motif) ligand 18 (CCL18) on urothelial carcinomas (UCs). Methods: Tumor tissues, paracancerous tissues, and serum were collected from 20 patients with UCs (diagnosed at Beijing Friendship Hospital, Capital Medical University). CCL18 was detected by immunohistochemistry and ELISA. PCR was used to measure the expression levels of CCL18 and mir-183, miR-128, mir-33a in UCs. We acquired exosomes from mesenchymal stem cells and synthesized exosomes overexpressing miR-128 (HMSC-128-EV). The effects of miR-128 on the migration and invasion abilities, apoptosis and epithelial-mesenchymal transition of BUC T24 cells were investigated by co-culturing HMSC-128-EV. The therapeutic potential of miR-128 on disease models was explored by injecting HMSC-128-EV into nude mice. Results: The expression of CCL18 in UCs was significantly higher than that in normal tissues (p < 0.05), and the serum level of CCL18 in patients with UC was significantly increased compared with those in healthy controls (p < 0.05). CCL18 overexpression or downregulation enhanced or suppressed the proliferation, migration and invasion of BUC T24 cells, resectively (p < 0.05). The exosome-transmitted miR-128 can inhibit cell proliferation (p < 0.05), invasion (p < 0.05), and migration (p < 0.05) in UCs, and these effects can be reversed by CCL18. In terms of apoptosis, miR-128 was able to promote the occurrence of BUC T24 apoptosis (p < 0.05), which can also be reversed by CCL18. In addition, miR-128 can inhibit the proliferation (p < 0.05) and metastasis (p < 0.05) of UCs in nude mice. Conclusion: The miR-128 inhibits the proliferation, invasion, migration of UCs, and promotes its apoptosis by regulating CCL18 secretion.
Highlights
Urothelial carcinomas (UCs) are the ninth most common form of manignancies, killing over 165,000 patients annually around the world (Rosenberg et al, 2016)
The exosome-transmitted miR-128 can inhibit cell proliferation (p < 0.05), invasion (p < 0.05), and migration (p < 0.05) in UCs, and these effects can be reversed by CCL18
MiR-128 was able to promote the occurrence of BUC T24 apoptosis (p < 0.05), which can be reversed by CCL18
Summary
Urothelial carcinomas (UCs) are the ninth most common form of manignancies, killing over 165,000 patients annually around the world (Rosenberg et al, 2016). Urinary bladder cancer accounts for 90–95% of all UCs and is the most common malignancy of UCs (Rouprêt et al, 2021). In terms of the histological type, urothelial and squamous carcinoma account for about 90 and 5% of all bladder cancers, respectively (Sjödahl et al, 2012). For the NMIBC, the recurrence rate is more than 50%, and disease progression will develop for 10–15% of patients (Têtu, 2009; Hedegaard et al, 2016). Cisplatin-based combination chemotherapy has been used as the standard treatment for unresectable and metastatic/ advanced UC, but patients who relapse after first-line treatment or have progression while receiving first-line treatment have a poor prognosis, and second-line chemotherapy shows only moderate efficacy, with an ORR of 12% and a median OS of 5–7 months (Kim and Seo, 2018). It is of great practical significance to develop drugs that can inhibit the proliferation and metastasis of UCs of the bladder
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