Dataset Information

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

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.

SUBMITTER: Garcia-Colmenero L

PROVIDER: S-EPMC7765332 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

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

García-Colmenero Lidia L González Jéssica J Sandoval Juan J Guillén Yolanda Y Diaz-Lagares Angel A Andrades Evelyn E Iglesias Arnau A Nonell Lara L Pujol Ramon Maria RM Bigas Anna A Espinosa Lluís L Gallardo Fernando F

Cells 20201215 12

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.<h4>Objective</h4>We studied here whether deregulation of miR-124 contributes to STAT3 pathway activation in CTCL.<h4>Methods</h4>We measured the effect of ectopic mir-124 expression in active phosph ...[more]

PMID: 33333886

Similar Datasets

Project description:Increasing evidences support a potential role for the Signal Transducer and Activator of Transcription-3 (STAT3) as a tumor driver in cutaneous T-cell lymphoma (CTCL). However, the mechanisms leading to STAT3 pathway activation in CTCL and how STAT3 activation contributes to lymphomagenesis remains primarily not enough explored. Recently, we found that miR-124, a known STAT3 regulator in cancer, is robustly silenced in Mycosis Fungoides (MF) tumor-stage and CTCL cell lines and we have herein studied whether deregulation of miR-124 contributes to activate STAT3 pathway in CTCL. Material and Methods: DNA methylation status of miR-124 and its expression levels in response to the DNA-demethylating agent azacitidine were evaluated in CTCL cell lines by pyrosequencing analysis. CTCL cell lines were transient transfected with a lentiviral vector encoding miR-124 and transfected cells were analyzed for phosphorylated STAT3 (P-STAT3) levels. The impact on STAT3 signaling was evaluated using expression microarray on CTCL cell lines in both conditions, miR-124 absent (malignant condition) versus miR-124 expressed (lentiviral transduction). Results: A significant promoter methylation and silencing of miR-124 in MF tumor samples and CTCL cell lines was detected. DNA methylation levels of miR-124 in CTCL cell lines were restored (and subsequently miR-124 were overexpressed) after DNA demethylation. Ectopic lentiviral expression of miR-124 downregulated STAT3 in the different CTCL cell lines. Genes differentially expressed regarding miR-124 regulation in CTCL cell lines indicated impact on known cell survival and function pathways and, particularly, intervention on miR-124 expression modulated different STAT3 pathway components. Conclusions: Our study deciphers a novel epigenetic mechanisms regulating STAT3 pathway in CTCL. This might contribute to a better understanding the molecular basis in CTCL development. Deregulation of STAT3 seems to have a major impact on cell survival in CTCL cell lines indicating the potential interest of targeting STAT3 with specific therapies.

Dataset Information

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

Objective

Methods

Results

Conclusions

Publications

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

Similar Datasets

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