The Type I IFN-Induced miRNA, miR-21

Abstract

The interferon (IFN) family of cytokines not only has antiviral properties at various steps in the viral replication cycle, but also anticancer activity through multiple pathways that include inhibiting cell proliferation, regulating cellular responses to inducers of apoptosis and modulating angiogenesis and the immune system. IFNs are known to induce their biological activity through the induction of protein encoding IFN-stimulated genes. However, recent studies have established that IFNs also induce the expression of microRNAs (miRNAs), which are small endogenous non-coding RNAs that suppress gene expression at the post-transcriptional level. MiRNAs play critical roles in tumorigenesis and have been implicated to act as either oncogenes or tumor suppressors in various human cancers. Therefore, IFN-induced miRNAs play an important role, not only in the host response to innate immune response to cancer, but also in the tumorigenic process itself. Furthermore, IFN-induced miRNAs may participate in and/or orchestrate antiviral defense in certain viral infections. In this review, we describe our recent studies on the induction of miR-21 by type I IFN, the role of the STAT3 and NFκB signaling pathways in IFN-induced miR-21 expression, the role of miR-21 in different cancers and the role of miR-21 in regulating the antiviral response.

Keywords: IFN; antiviral; cancer; miRNAs.

Figure 1

The role of miR-21 in the antiviral action of IFN. Empty vector (EV)- and antagomiR-21 transduced (miR-21 KD) human DU145 prostate cancer cells or murine B16 melanoma cells were added to 48-well plates (1 × 10⁴ cells/well). After incubation overnight, triplicate wells were treated with 0, 1, 3, 10, 30 or 100 units/mL of human IFNα or murine IFNβ, respectively, for an additional 24 h. The cells were then infected with a recombinant vesicular stomatitis virus expressing firefly luciferase (rVSV-Luc) as the readout for viral replication (generously provided by Dr. Sean Whelan, Harvard Medical School) at a multiplicity of infection of one. At 6 h post-infection, cells were lysed by the addition of 65 μL of lysis buffer, and luciferase activity in the cell lysate (10 μL) was determined.

Figure 2

The effect of miR-21 deficiency on the sensitivity of mouse embryo fibroblasts to the antiviral action of IFN. Mouse embryo fibroblasts from miR-21 knockout mice or their wild-type littermates (generously provided by Dr. Mark Hatley, St. Jude Children’s Research Hospital, Memphis, TN, USA) were added to 48-well plates (1 × 10⁴ cells/well). After incubation overnight, triplicate wells were treated with 0, 1, 3, 10, 30 or 100 units/mL of murine IFN for an additional 24 h. The cells were then infected with rVSV-Luc at a multiplicity of infection of one. At 6 h post-infection, cells were lysed by the addition of 65 μL of lysis buffer, and luciferase activity in the cell lysate (10 μL) was determined.