MicroRNAs and STAT interplay

Abstract

MicroRNA (miR) are emerging as important gene expression regulators often involved in a variety of pathogenesis such as cancers and autoimmunity. Signal transducers and activators of transcription (STAT) proteins are the principle signaling proteins for many cytokines and growth factors, thereby play a critical role in regulating immune cell homeostasis, differentiation and cellular functions. In this review, we discuss recent advances in the field demonstrating active interactions between STATs and miRs, with our primary focus on the promotion and inhibition of immune cells and cancer. Additionally, we review the reciprocal regulations between STATs and miR, and discuss how we can use this knowledge in the context of diseases. For example, recent findings related to STAT1 and miR-155 support the presence of a positive feedback loop of miR-155 and STAT1 in response to inflammatory signals or infection. STAT3 is known to play critical roles in tumorigenesis and cancer-induced immunosuppression. There is a growing body of evidence demonstrating that STAT3 directly activates miR-21, one of miRs that promote cancer cell survival and proliferation. While some miRs directly regulate STATs, there are findings demonstrating indirect STAT regulation by miRs also mediate important biological mechanisms. Therefore, further research is warranted to elucidate significant contributions made by direct and indirect miR–STAT mechanisms. As we learn more about miR pathways, we gain the opportunity to manipulate them in cancer cells to slow down growth or increase their susceptibility anti-tumor immunity.

Introduction

MicroRNA (miR) are emerging as important gene expression regulators often involved in a variety of pathogenesis such as cancers and autoimmunity. Primary miR transcripts (pri-miR) are transcribed by RNA polymerase II and RNA polymerase III [1], and contain the mature miR in a hairpin structure. The pri-miR hairpin is then cleaved by the class 2 RNase III enzyme, Drosha and the remaining precursor miR (pre-miR) is transported out of the nucleus by Exportin-V. The RNase III superfamily member Dicer then cleaves the hairpin loop structure leaving two single strands of RNA. After one strand is degraded, the other mature miR of about 22 nucleotides is incorporated into an RNA-induced silencing complex (RISC). Binding of the mature miR seed sequence to partial or exact complementary regions of 3′ untranslated region (UTR) on mRNA results in translational inhibition or mRNA degradation, respectively [2], [3]. miR are predicted to regulate up to 90% of human genes making them an important element of cellular processes [4].

Signal transducers and activators of transcription (STAT) proteins are the principle signaling proteins of many cytokines and growth factors in mammals [5]. STATs play a critical role in regulating immune cell homeostasis, differentiation and cellular functions. There are 7 STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT6 and the isoforms, STAT5a and STAT5b), each with established roles in immune cell functioning (Table 1). The key regulation of STATs is mediated by phosphorylation, typically by Janus kinases (JAKs). STAT1 and 2 respond to interferons (IFNs), thereby promote IFN-stimulated genes and anti-viral immunity [6], [7]. STAT3 responds to factors including IL-6, IL-10 and VEGF and is involved in T-helper cell (Th)17 and Treg cell development and tumorigenesis [8], [9]. STAT4 and STAT6 control Th1 and Th2 cell differentiation in response to IL-12 and IL-4/13, respectively [10], [11]. Finally, STAT5a and STAT5b are involved in NK cell activity, IL-2 induced T-cell proliferation and have been suggested to play a role in oncogenesis [12], [13]. Due to the large involvement of STATs in a variety of cell processes, it is critical that their activity is tightly regulated.

In this review, we discuss recent advances in the field demonstrating active interactions between STATs and miRs. While providing comprehensive overview of this subject, we address our primary focus to the promotion and inhibition of immune cells and cancer. Additionally, we will review the reciprocal regulations between STATs and miR, and discuss how we can use this knowledge in the context of diseases. Most of the published findings on miR/STAT regulation have occurred over the past few years, and to our knowledge, this is the first review specifically focused on this topic.