Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma
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Bibliographic record
Abstract
// Nina A. Sibbesen 1 , Katharina L. Kopp 1 , Ivan V. Litvinov 2 , Lars Jønson 3 , Andreas Willerslev-Olsen 1 , Simon Fredholm 1 , David L. Petersen 1 , Claudia Nastasi 1 , Thorbjørn Krejsgaard 1 , Lise M. Lindahl 4 , Robert Gniadecki 5 , Nigel P. Mongan 6 , Denis Sasseville 2 , Mariusz A. Wasik 7 , Lars Iversen 4 , Charlotte M. Bonefeld 1 , Carsten Geisler 1 , Anders Woetmann 1 and Niels Odum 1 1 Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark 2 Division of Dermatology, McGill University Health Centre, Montréal, Quebec, Canada 3 Departmen of Molecular Medicine, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark 4 Department of Dermatology, Aarhus University Hospital, Skejby, Aarhus, Denmark 5 Departmen of Dermatology, Copenhagen University Hospital, Bispebjerg, Copenhagen, Denmark 6 Faculty of Medicine and Health Science, School of Veterinary Medicine and Science, University of Nottingham, Loughborough, United Kingdom 7 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA Correspondence to: Niels Odum, email: // Keywords : miR-22, cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF), STAT3, STAT5, JAK3 Received : March 09, 2015 Accepted : April 22, 2015 Published : May 12, 2015 Abstract Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it