MiR-155 meets the JAK/STAT pathway

Abstract

microRNA-155 (miR-155) is one of the most studied miRNAs and the first one to be described as oncogenic.1 Encoded by its host gene, MIR155HG, also referred to as BIC (B cell integration cluster), was first found accumulated in B-cell lymphoma by Eis et al.2 Soon after, miR-155 overexpression was observed in a long list of both hematological and solid-tissue cancers, where it was found to promote genomic instability, proliferation, and survival of malignant cells.3 These properties have led to miR-155 now being referred to as an “oncomiR.” Simultaneously, data emerged suggesting that miR-155 plays an absolutely crucial role in development and activation of several types of immune cells, including B and T cells.4 Thus, this little molecule is one of those players that make apparent the link between inflammation and cancer, postulated by Virchow so many years ago: transient elevation of miR-155 levels is observed and necessary for functioning of immune cells; however, a chronically increased expression of miR-155 is often found in cancer, and miR-155 expression alone is sufficient to trigger malignant transformation.1-3 The idea of miR-155 as a bridge between inflammation and cancer is supported by the fact that miR-155 can be induced by several inflammatory stimuli,3 and among its targets are tumor suppressors and anti-inflammatory molecules.5 However, miRNAs function as fine-tuners of protein expression and therefore the signals triggering expression of a miRNA are tightly regulated and seem to be highly context-dependent. Induction pathways as well as target genes vary among different cell types, tissues, or diseases. To understand the oncogenic properties of miR-155 expression, it is important to elucidate this variety of pathways in order to determine which stimuli regulate this miRNA that has the potential to transform cells and seems to be deregulated in so many cancers. Initially, a large fraction of the research on miRNAs primarily comprised expression profiles, revealing differential expression of specific miRNAs in various disease settings. Only recently research has started to focus on regulation and function of miRNAs. One would think that, miR-155 being a necessary component required for normal immune function, more studies would have investigated the specific influence of key cytokines on its expression, but surprisingly little is known about miR-155 modulation in response to cytokine stimulation. A new study by Kopp et al.6 now connects expression of miR-155 to JAK/STAT signaling. In a recent issue of Cell Cycle, Kopp et al. report that the MIR155HG is a transcriptional target of STAT5, a well-known malefactor in the pathogenesis of lymphoma as well as several other cancers. Kopp et al. show that in cutaneous T-cell lymphoma (CTCL) cells, STAT5 (persistently activated in a majority of patients) directly binds to the BIC promoter and induces miR-155 expression. In CTCL T cell lines and primary cells, IL-2 or IL-15-induced (IL2Rb cytokines that signal through STAT5) constitutive STAT5 activation results in an increased transcription of BIC. Conversely, knockdown of STAT5 entails a decrease in miR-155 in the malignant cells as well as inhibits their proliferative capacity, an effect that is paralleled by direct inhibition of miR-155. This points toward a functional role of miR-155 in maintaining malignant proliferation. Furthermore, the fact that STAT5-dependent miR-155 induction was also observed in non-malignant T cells and PBMCS points toward a general (non-CTCL-specific) pathway of miR-155 regulation. Chronic inflammation involving a disturbed expression of miRNAs, including miR-155, is a hallmark of CTCL,7,8 and the JAK/STAT pathways have long been known to be crucial players in the pathogenesis of leukemia and lymphoma. This recent study by Kopp et al. connects expression of an oncogenic miRNA to cytokine (or aberrant) signaling of the JAK/STAT pathway and sheds light on the particular role of STAT5 in the induction of oncogenic molecules, thereby further clarifying the link between inflammation and cancer. It remains to be investigated if the same mechanism is also working in other malignancies.