Transcriptional repression of miR-200 family members by Nanog in colon cancer cells induces epithelial-mesenchymal transition (EMT).
Nanog is an important embryonic stem cell (ESC) gene that does not function as a classical oncogene, but needs to cooperate with other molecules to potentiate tumorigenic activity. The question addressed by the present study was whether a miRNA link exists between Nanog and epithelial-mesenchymal transition (EMT)-mesenchymal-epithelial transition (MET) plasticity. Here, we found that Nanog mRNA expression level was inversely correlated with miR-200c and miR-200b expression levels in colon cancer cell lines and human colorectal cancer tissues. Forced Nanog expression in low-Nanog colon cancer cells inhibited miR-200c and miR-200b expression, and interfered Nanog expression in high-Nanog colon cancer cells promoted miR-200c and miR-200b expression. Furthermore, we confirmed that Nanog directly repressed transcription of the miR-200c and miR-200b genes, and miR-200c and miR-200b mediated Nanog-induced EMT occurrence. Luciferase and ChIP assays determined that Nanog bound directly to the potential Nanog binding sites in the miR-200c and miR-200b promoters and repressed their transcription. In conclusion, our findings suggest that Nanog modulates EMT-MET plasticity by regulating miR-200 clusters via a direct transcriptional mechanism, and the Nanog-miR-200 axis may be a good therapeutic target for CRC control.
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Qiong
Q
Pan
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Linkun
L
Meng
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Jun
J
Ye
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Xiaolong
X
Wei
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Yangyang
Y
Shang
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Yin
Y
Tian
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Yonghong
Y
He
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Zhihong
Z
Peng
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Lei
L
Chen
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China.
Wensheng
W
Chen
Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China. Electronic address: bianxiuwu@263.net.
Xiuwu
X
Bian
Department of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China. Electronic address: rongquanw@hotmail.com.
Rongquan
R
Wang
D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D000071317:Nanog Homeobox Protein / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden
C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D012333:RNA, Messenger
Colon cancer; Epithelial–mesenchymal transition; Mesenchymal–epithelial transition; Nanog; Transcriptional regulation; miRNA