miR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively.
miRNAs typically downregulate the expression of target genes by binding to their 3'UTR, and dysregulation of miRNAs may contribute to tumorigenesis. Here, we found that miR-346 and miR-138 competitively bind to a common region in the 3'UTR of hTERT mRNA and have opposite effects on the expression and function of hTERT in human cervical cancer cells. Furthermore, G-rich RNA sequence binding factor 1 (GRSF1) mediates the miR-346-dependent upregulation of hTERT by binding to the miR-346 middle sequence motif (CCGCAU) which forms a "bulge loop" when miR-346 is bound to the hTERT 3'UTR, facilitating the recruitment of hTERT mRNA to ribosomes to promote translation in an AGO2-independent manner. Conversely, miR-138 suppresses hTERT expression in an AGO2-dependent manner. Interestingly, replacement of the miR-138 middle sequence with that of miR-346 results in an upregulation of hTERT expression in a GRSF1-dependent manner. Moreover, miR-346 depends on GRSF1 to upregulate another target gene, activin A receptor, type IIB (ACVR2B), in which miR-346 "CCGCAU" motif is essential. These findings reveal novel mechanisms of miRNA-mediated upregulation of target gene expression and describe the coordinated action of multiple miRNAs to control the fate of a single target mRNA through binding to its 3'UTR.
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Ge
G
Song
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Renjie
R
Wang
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Junfei
J
Guo
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Xuyuan
X
Liu
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Fang
F
Wang
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Ying
Y
Qi
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Haiying
H
Wan
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Min
M
Liu
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Xin
X
Li
Tianjin Life Science Research Center, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Hua
H
Tang
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D039102:Poly(A)-Binding Proteins / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*
D020413:3' Untranslated Regions; C466422:AGO2 protein, human; D060565:Argonaute Proteins; C088356:GRSF1 protein, human; C546110:MIRN138 microRNA, human; C560923:MIRN346 microRNA, human; D035683:MicroRNAs; D039102:Poly(A)-Binding Proteins; C509186:TERT protein, human; D019098:Telomerase