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c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma

1
Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital, Chia-Yi 600, Taiwan
2
Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi 62247, Taiwan
3
Department of Biomedical Sciences, National Chung Cheng University, Min Hsiung, Chia-Yi 62102, Taiwan
4
Epigenomics and Human Disease Research Center, National Chung Cheng University, Min Hsiung, Chia-Yi 62102, Taiwan
5
Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan
6
Center for Innovative Research on Aging Society (CIRAS), National Chung Cheng University, Min-Hsiung, Chia-Yi 62102, Taiwan
7
Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(10), 1457; https://doi.org/10.3390/cancers11101457
Received: 22 September 2019 / Accepted: 25 September 2019 / Published: 28 September 2019
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. View Full-Text
Keywords: miR-34a; CD44; c-Myc; ceRNA; urothelial carcinoma miR-34a; CD44; c-Myc; ceRNA; urothelial carcinoma
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Chen, P.-C.; Yu, C.-C.; Huang, W.-Y.; Huang, W.-H.; Chuang, Y.-M.; Lin, R.-I.; Lin, J.M.J.; Lin, H.-Y.; Jou, Y.-C.; Shen, C.-H.; Chan, M.W.Y. c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma. Cancers 2019, 11, 1457.

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