Abstract
To perform their regulatory functions, microRNAs (miRNAs) must assemble with any of the four mammalian Argonaute (Ago) family of proteins, Ago1–4, into an effector complex known as the RNA-induced silencing complex (RISC). While the mature miRNA guides the RISC complex to its target mRNA, the Ago protein represses mRNA translation. The specific roles of the various Ago members in mediating miRNAs activity, however, haven’t been clearly established. In this study, we investigated the contribution of Ago2, the only human Ago protein endowed with nuclease activity, to the function of tumor-suppressor miR-145-5p in breast cancer (BC). We show that miR-145-5p and Ago2 protein are concomitantly downregulated in BC tissues and that restoration of miR-145-5p expression in BC cells leads to Ago2 protein induction through the loosening of Ago2 mRNA translational repression. Functionally, miR-145-5p exerts its inhibitory activity on cell migration only in presence of Ago2, while, upon Ago2 depletion, we observed increased miR-145/Ago1 complex and enhanced cell motility. Profiling by microarray of miR-145-5p target mRNAs, in BC cells depleted or not of Ago2, revealed that miR-145-5p drives Ago2-dependent and -independent activities. Our results highlight that the Ago2 protein in cancer cells strictly dictates miR-145-5p tumor suppressor activity.
Highlights
MicroRNAs are small non-coding RNAs able to regulate gene expression at post-transcriptional level
The miRNAs loaded in the RNA-induced silencing complex (RISC) complex usually function as negative regulators of gene expression, mainly by targeting the 3’-untranslated region (UTR) of their target mRNAs
Results miR-145-5p upregulates Ago[2] expression As mentioned, downregulation of tumor suppressor miR-145-5p is a frequent event in human tumors, included breast cancer, and leads to the increased expression of its target mRNAs
Summary
MicroRNAs (miRNAs) are small non-coding RNAs able to regulate gene expression at post-transcriptional level. They control cell fate decision in several developmental programs and their deregulation has been associated with tumor progression[1]. It has been extensively demonstrated that miRNAs may behave as oncogenes or tumor To perform their regulatory functions, miRNAs must assemble with any of the four mammalian Argonaute (Ago) family of proteins, Ago[1,2,3,4], into an effector complex known as the RNA-induced silencing complex (RISC)[2]. Despite a remarkable homology that extends to the PIWI domains among all four human Ago proteins, Argonaute[2] (Ago2) is the only human Ago protein endowed with nuclease activity[5,6,7,8,9,10,11]
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