Abstract
MicroRNAs (miRNAs) have been shown to play a crucial role in the progression of human cancers, including urothelial carcinoma (UC), the sixth-most common cancer in the world. Among them, miR-34a has been implicated in the regulation of cancer stem cells (CSCs); however, its role in UC has yet to be fully elucidated. In this study, bioinformatics and experimental analysis confirmed that miR-34a targets CD44 (a CSC surface marker) and c-Myc (a well-known cell cycle regulator) in UC. We found that, surprisingly, most UC cell lines and patient samples did express miR-34a, although epigenetic silencing by promoter hypermethylation of miR-34a expression was observed only in UMUC3 cells, and a subset of patient samples. Importantly, overexpression of c-Myc, a frequently amplified oncogene in UC, was shown to upregulate CD44 expression through a competing endogenous RNA (ceRNA) mechanism, such that overexpression of the c-Myc 3′UTR upregulated CD44, and vice versa. Importantly, we observed a positive correlation between the expression of c-Myc and CD44 in clinical samples obtained from UC patients. Moreover, overexpression of a dominant-negative p53 mutant downregulated miR-34a, but upregulated c-Myc and CD44, in UC cell lines. Functionally, the ectopic expression of miR-34a was shown to significantly suppress CD44 expression, and subsequently, suppression of cell growth and invasion capability, while also reducing chemoresistance. In conclusion, it appears that aberrant promoter methylation, and c-Myc-mediated ceRNA mechanisms, may attenuate the function of miR-34a, in UC. The tumor suppressive role of miR-34a in controlling CSC phenotypes in UC deserves further investigation.
Highlights
Urothelial carcinoma (UC) is the sixth most common cancer in the world, with a high incidence in southwestern Taiwan
Overexpression of miR-34a was shown to reduce both mRNA and protein of CD44 in UMUC3 cells (Figure 2C). These results suggest that miR-34a targets c-Myc and CD44 in urothelial carcinoma (UC)
We examined the competing endogenous RNA (ceRNA) mechanism, in vivo, by assessing the expression of c-Myc and in samples obtained from 55 UC patients
Summary
Urothelial carcinoma (UC) is the sixth most common cancer in the world, with a high incidence in southwestern Taiwan. The majority of UCs are found in the urinary bladder, while tumors from the upper urinary tract (ureter or renal pelvis, known as UTUC) account for 5–10% of all UCs worldwide [1], but 20% in Taiwan [2]. One of the major challenges in treating UC is dealing with the high recurrence rate of superficial cancers, and more than 40% of all UC patients will recur within 5 years, even after surgical treatment [3]. This may be attributed to the presence of drug-resistant cancer stem cells (CSCs), which are characterized by the presence of CD44 [4,5]. Elucidating the molecular mechanism(s) underlying the formation of CSCs in UC could lead to the development of novel therapeutic methods to deal with this deadly disease
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