Lidia García-Colmenero1, Jéssica González2,3, Juan Sandoval4, Yolanda Guillén3, Angel Diaz-Lagares5, Evelyn Andrades1,2, Arnau Iglesias2,3, Lara Nonell6, Ramon Maria Pujol1,2, Anna Bigas3, Lluís Espinosa3, Fernando Gallardo1,2. 1. Department of Dermatology, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Universitat Autònoma Barcelona, Carrer del Dr. Aiguader, 88, 08003 Barcelona, Spain. 2. Cancer Research Program Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain. 3. Stem Cells and Cancer Research Laboratory-IMIM, CIBERONC, 08003 Barcelona, Spain. 4. Epigenomics Unit, IIS, La Fe, 46026 Valencia, Spain. 5. 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. 6. Microarray Department-IMIM, 08003 Barcelona, Spain.
Abstract
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.
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.
Entities:
Keywords:
JAK/STAT (janus kinase/signal transducer and activator of transcription); STAT3 (signal transducer and activator of transcription-3); Sézary syndrome; cutaneous T-cell lymphoma; miR-124; mycosis fungoides
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