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

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...

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Autores principales: Chen, Pie-Che, Yu, Chih-Chia, Huang, Wen-Yu, Huang, Wan-Hong, Chuang, Yu-Ming, Lin, Ru-Inn, Lin, Jora M. J., Lin, Hon-Yi, Jou, Yeong-Chin, Shen, Cheng-Huang, Chan, Michael W. Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826510/
https://www.ncbi.nlm.nih.gov/pubmed/31569404
http://dx.doi.org/10.3390/cancers11101457
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author Chen, Pie-Che
Yu, Chih-Chia
Huang, Wen-Yu
Huang, Wan-Hong
Chuang, Yu-Ming
Lin, Ru-Inn
Lin, Jora M. J.
Lin, Hon-Yi
Jou, Yeong-Chin
Shen, Cheng-Huang
Chan, Michael W. Y.
author_facet Chen, Pie-Che
Yu, Chih-Chia
Huang, Wen-Yu
Huang, Wan-Hong
Chuang, Yu-Ming
Lin, Ru-Inn
Lin, Jora M. J.
Lin, Hon-Yi
Jou, Yeong-Chin
Shen, Cheng-Huang
Chan, Michael W. Y.
author_sort Chen, Pie-Che
collection PubMed
description 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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spelling pubmed-68265102019-11-18 c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma Chen, Pie-Che Yu, Chih-Chia Huang, Wen-Yu Huang, Wan-Hong Chuang, Yu-Ming Lin, Ru-Inn Lin, Jora M. J. Lin, Hon-Yi Jou, Yeong-Chin Shen, Cheng-Huang Chan, Michael W. Y. Cancers (Basel) Article 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. MDPI 2019-09-28 /pmc/articles/PMC6826510/ /pubmed/31569404 http://dx.doi.org/10.3390/cancers11101457 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Pie-Che
Yu, Chih-Chia
Huang, Wen-Yu
Huang, Wan-Hong
Chuang, Yu-Ming
Lin, Ru-Inn
Lin, Jora M. J.
Lin, Hon-Yi
Jou, Yeong-Chin
Shen, Cheng-Huang
Chan, Michael W. Y.
c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma
title c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma
title_full c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma
title_fullStr c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma
title_full_unstemmed c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma
title_short c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma
title_sort c-myc acts as a competing endogenous rna to sponge mir-34a, in the upregulation of cd44, in urothelial carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826510/
https://www.ncbi.nlm.nih.gov/pubmed/31569404
http://dx.doi.org/10.3390/cancers11101457
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