c-Myc和CD44在尿路上皮癌中互為競爭性內源RNA並同時受到miR-34a調控
沈正煌1,2,*、陳丕哲1、余芝嘉3、黃雯宇4、黃琬紅4、莊育銘4,5、林如胤3、林孟儒4、林宏益3、
周詠欽1、陳永恩4,5,6,7,*
1嘉義基督教醫院泌尿外科; 2亞洲大學營養與保健生技學系; 3大林慈濟醫院放射腫瘤科; 4中正大學生醫系, 5表觀基因體暨人類疾病研究中心, 6高齡跨域創新研究中心; 7高雄醫學大學環境醫學研究中心
c-Myc Acts as a Competing Endogenous RNA to Sponge miR-34a, in the Upregulation of CD44, in Urothelial Carcinoma
Cheng-Huang Shen1,2,*, Pie-Che Chen1, Chih-Chia Yu3, Wen-Yu Huang4, Wan-Hong Huang,4,5, Yu-Ming Chuang4,5, Ru-Inn Lin3, Jora M. J. Lin4, Hon-Yi Lin3, Yeong-Chin Jou1 and Michael W. Y. Chan 4,5,6,7,*
1Department of Urology, Ditmanson Medical Foundation Chiayi Christian Hospital; 2Department of Health and Nutrition Biotechnology, Asia University; 3Department of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation; 4Department of Biomedical Sciences, 5Epigenomics and Human Disease Research Center, 6Center for Innovative Research on Aging Society (CIRAS), National Chung Cheng University; 7 Research Center for Environmental Medicine, Kaohsiung Medical University
Purpose: 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. Consequently, our objective in this study was to determine the role of epigenetic modification in the expression of miR-34a, and its target genes, in UC
Materials and Methods: In this study, bioinformatics and experimental analysis were used to confirm that miR-34a targets CD44 (a CSC surface marker) and c-Myc (a well-known cell cycle regulator) in UC.
Results: 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.
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.