MiR-346 and miR-138 competitively regulate hTERT in GRSF1- and AGO2-dependent manners, respectively.

Ge Song,Min Liu,Renjie Wang,Ying Qi,Junfei Guo,Xuyuan Liu,Hua Tang,Haiying Wan,Xin Li,Fang Wang

doi:10.1038/srep15793

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Journal: Scientific Reports	Publication Date: Oct 28, 2015
Citations: 74	License type: CC BY 4.0

Affiliation: Tianjin Medical University

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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.

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MiRNAs are a class of endogenously conserved small RNAs that regulate target gene expression by affecting mRNA translation and stability or by modulating the promoter activity of target genes1,2. miRNAs may control the majority of human genes, which are involved in a wide variety of biological and pathogenic processes, including cancers[3,4,5,6]
Human cervical cancer is a leading disease in women worldwide, and human telomerase reverse transcriptase (hTERT) is generally upregulated in this cancer32. hTERT plays a critical role in tumorigenesis and immortalized cells through its telomere-dependent and -independent activity[20,33]
The reactivation of hTERT expression is a critical step in carcinogenesis, which is required to maintain the rapid proliferation of cancer cells, and hTERT

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MiRNAs are a class of endogenously conserved small RNAs that regulate target gene expression by affecting mRNA translation and stability or by modulating the promoter activity of target genes1,2. miRNAs may control the majority of human genes, which are involved in a wide variety of biological and pathogenic processes, including cancers[3,4,5,6]. There is evidence that multiple miRNAs target the same region in the 3′ UTRs to regulate target genes expression[15]. Despite the opposite effects on hTERT expression, the miR-346 and miR-138 binding sites are in a common region of the hTERT 3′ UTR, in which the coordinated regulation results in the upregulation of hTERT and contributes to the growth of cervical cancer cells. The critical roles of miR-346 “CCGCAU” motif and GRSF1 are further confirmed through the studies of activin A receptor, type IIB (ACVR2B), SMAD family member 3 (SMAD3) and miR-138 middle sequence motif These findings shed light on miRNA-mediated upregulation of target mRNAs through 3′ UTR binding and provide novel insight into the mechanisms by which multiple miRNAs modulate the expression of a single mRNA

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