期刊
CANCERS
卷 11, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/cancers11101457
关键词
miR-34a; CD44; c-Myc; ceRNA; urothelial carcinoma
类别
资金
- Ministry of Science and Technology, Taiwan [MOST 104-2320-B-194-001-MY3, 106-2923-B-194-001-MY3, 108-2314-B-194-003-MY2]
- Ditmanson Medical Foundation Chiayi Christian Hospital, Taiwan [R107-001, R101-9]
- Center for Innovative Research on Aging Society (CIRAS) from The Featured Areas Research Center Program by Ministry of Education (MOE) in Taiwan
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.
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