Epigenetic Silencing of Tumor Suppressor miR-124 Directly Supports STAT3 Activation in Cutaneous T-Cell Lymphoma

Cells

Angel Diaz-Lagares¹  Arnau Iglesias²  Jéssica González²  Fernando Gallardo³  Lidia García-Colmenero³  Evelyn Andrades³  RamonMaria Pujol³  Juan Sandoval⁴  Lara Nonell⁵  Yolanda Guillén⁶  Lluís Espinosa⁶  Anna Bigas⁶ 

[1] Cancer Epigenomics, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), CIBERONC, 15706 Santiago de Compostela, Spain;Cancer Research Program Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain;Department of Dermatology, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autònoma Barcelona, Carrer del Dr. Aiguader, 88, 08003 Barcelona, Spain;Epigenomics Unit, IIS, La Fe, 46026 Valencia, Spain;Microarray Department-IMIM, 08003 Barcelona, Spain;Stem Cells and Cancer Research Laboratory-IMIM, CIBERONC, 08003 Barcelona, Spain;

关键词: cutaneous T-cell lymphoma;    mycosis fungoides;    Sézary syndrome;    STAT3 (signal transducer and activator of transcription-3);    JAK/STAT (janus kinase/signal transducer and activator of transcription);    miR-124;   

DOI  :  10.3390/cells9122692

来源: DOAJ

【 摘 要 】

Increasing evidence supports a potential role for STAT3 as a tumor driver in cutaneous T-cell lymphomas (CTCL). The mechanisms leading to STAT3 activation are not fully understood; however, we recently found that miR-124, a known STAT3 regulator, is robustly silenced in MF tumor-stage and CTCL cells. Objective: We studied here whether deregulation of miR-124 contributes to STAT3 pathway activation in CTCL. Methods: We measured the effect of ectopic mir-124 expression in active phosphorylated STAT3 (p-STAT3) levels and evaluated the transcriptional impact of miR-124-dependent STAT3 pathway regulation by expression microarray analysis. Results: We found that ectopic expression of miR-124 results in massive downregulation of activated STAT3 in different CTCL lines, which resulted in a significant alteration of genetic signatures related with gene transcription and proliferation such as MYC and E2F. Conclusions: Our study highlights the importance of the miR-124/STAT3 axis in CTCL and demonstrates that the STAT3 pathway is regulated through epigenetic mechanisms in these cells. Since deregulated STAT3 signaling has a major impact on CTCL initiation and progression, a better understanding of the molecular basis of the miR-124/STAT3 axis may provide useful information for future personalized therapies.

【 授权许可】

Unknown