Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia

Abstract

Interleukin‑9 (IL‑9) can function as both a positive and negative regulator of immune response, however the role of IL‑9 in tumor immunity is poorly understood. Chronic lymphocytic leukemia (CLL) is the most common chronic lympho‑proliferative disorder. Twenty CLL patients from 2010 to 2011 were recruited in the study. Expression and phosphorylation of transcription factor STAT3 and differential microRNAs (miRs) in peripheral blood mononuclear cells (PBMCs) from CLL patient samples were analyzed. In a previous study, we found a high level of IL‑9 in CLL patients. Concomitantly, overexpression of pSTAT3, miR‑155, and miR‑21 were observed in PBMCs from CLL patients in the present study. To elucidate whether there was interaction among IL‑9, STAT3, miR‑155, and miR‑21, MEC‑1 cells were used for further study. Our results revealed that there was no detectable IL‑9 in the culture medium of MEC‑1 cells. However, the IL‑9 protein could be detected using western blotting in MEC‑1 cells. Notably, when recombinant human IL‑9 (rIL‑9) was added to the medium of culturing MEC‑1 cells, the expression levels of pSTAT3 and IL‑9 in MEC‑1 cells were increased in a time‑dependent manner, which could be blocked by STAT3 inhibitor. Both miR‑155 and miR‑21 could increase IL‑9 expression, which could also be suppressed by the inhibitor of STAT3. Our data indicated that the existence of the novel 'extracellular IL‑9/pSTAT3/miR‑155/miR‑21/intracellular IL‑9' positive feedback system in CLL cells, provides a novel insight in the pathogenesis and possible therapeutic strategy of CLL.

Preclinical Evidence of STAT3 Inhibitor, Pacritinib, Overcomes Temozolomide Resistance via Down-Regulating miR-21-enriched Exosomes from M2 Glioblastoma-Associated Macrophages

“…Thus, we evaluated the feasibility of using small-molecule agent which may indirectly increase miR-21 level to convey therapeutic functions in GBM. STAT3 signaling has been shown to be important in GBM tumorigenesis as well as linked to the expression of miR-21 [17,31,32]. Based on these premises, we evaluated pacritinib, a recent FDA-approved inhibitor of STAT3/JAK2 signaling for treating myelofibrosis [33,34].…”

“…An elevated STAT3 signaling has been attributed to the malignancy of GBM and the generation of glioma stem cells [16]. In addition, increased STAT3 signaling is associated with the increased miR-21 level in the promotion of tumorigenesis [17,18]. Based on this premises, we examined a clinical STAT3 inhibitor, pacritinib for its potential GBM inhibitory effects.…”

The Important Role of STAT3 in Chronic Lymphocytic Leukaemia Biology

“…Further, STAT3 regulates cytokine production in CLL cells. STAT3 was found to regulate the secretion of IL-9 and IL-10 in CLL cells [18,30]. STAT3-mediated translational upregulation of miR-155 and miR-21 promoted IL-9 secretion [18].…”

“…STAT3 plays a role in promoting tumourigenesis of CLL where it represents a key pathway involved in the growth and survival of CLL cells [8,9,15,16]. In CLL, STAT3 messenger RNA (mRNA) expression is significantly higher compared to healthy B-lymphocytes [17][18][19]. Therefore, the regulation of STAT3 activity is highly dysregulated in CLL cells.…”

“…STAT3 was found to regulate the secretion of IL-9 and IL-10 in CLL cells [18,30]. STAT3-mediated translational upregulation of miR-155 and miR-21 promoted IL-9 secretion [18]. Concerning IL-10, the CXCL12-CXCR4-STAT3 axis regulates IL-10 production in CLL cells and their ability to suppress T-cell effector function [30].…”