STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma.

Abstract

The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive. Recent discoveries indicate that the oncogenic microRNA miR-155 is overexpressed in affected skin from CTCL patients. Here, we address what drives the expression of miR-155 and investigate its role in the pathogenesis of CTCL. We show that malignant T cells constitutively express high levels of miR-155 and its host gene BIC (B cell integration cluster). Using ChIP-seq, we identify BIC as a target of transcription factor STAT5, which is aberrantly activated in malignant T cells and induced by IL-2/IL-15 in non-malignant T cells. Incubation with JAK inhibitor or siRNA-mediated knockdown of STAT5 decreases BIC/miR-155 expression, whereas IL-2 and IL-15 increase their expression in cell lines and primary cells. In contrast, knockdown of STAT3 has no effect, and BIC is not a transcriptional target of STAT3, indicating that regulation of BIC/miR-155 expression by STAT5 is highly specific. Malignant proliferation is significantly inhibited by an antisense-miR-155 as well as by knockdown of STAT5 and BIC.   In conclusion, we provide the first evidence that STAT5 drives expression of oncogenic BIC/miR-155 in cancer. Moreover, our data indicate that the STAT5/BIC/miR-155 pathway promotes proliferation of malignant T cells, and therefore is a putative target for therapy in CTCL.

• Authors: Katharina L Kopp, Ulrik Ralfkiaer, Lise Mette R Gjerdrum, Rikke Helvad, Ida H Pedersen, Thomas Litman, Lars Jønson, Peter H Hagedorn, Thorbjørn Krejsgaard, Robert Gniadecki, Charlotte M Bonefeld, Lone Skov, Carsten Geisler, Mariusz A Wasik, Elisabeth Ralfkiaer, Niels Ødum, Anders Woetmann
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 12 Issue 12 Pg. 1939-47 (Jun 15 2013) ISSN: 1551-4005 [Electronic] United States
• PMID: 23676217 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN155 microRNA, human
• MicroRNAs
• STAT3 Transcription Factor
• STAT5 Transcription Factor

Topics

• Blotting, Western
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• Electrophoresis, Polyacrylamide Gel
• Flow Cytometry
• Humans
• In Vitro Techniques
• Lymphoma, T-Cell, Cutaneous (genetics, metabolism)
• MicroRNAs (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (genetics, metabolism)
• STAT5 Transcription Factor (genetics, metabolism)