Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".