miRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc
Bibliographic record
Abstract
// Manujendra N. Saha 1, 2,*,† , Jahangir Abdi 1, 2, * , Yijun Yang 1, 2,3 , Hong Chang 1, 2, 4 1 Division of Molecular and Cellular Biology, Toronto General Research Institute, Toronto, Ontario, Canada 2 Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada 3 Department of Applied Chemistry, School of Chemical Engineering and Technology, Tianjin University, Tianjin, P. R. China 4 Department of Laboratory Hematology and Medical Oncology, University Health Network, Toronto, Ontario, Canada † Current address: Department of Surgery, London Health Sciences Center, London, Ontario, Canada * These authors have contributed equally to this work Correspondence to: Hong Chang, e-mail: Hong.Chang@uhn.on.ca Keywords: myeloma, miRNA-29a, Myc, apoptosis Received: September 03, 2015 Accepted: January 03, 2016 Published: January 11, 2016 ABSTRACT The proto-oncogene c-Myc plays substantial role in multiple myeloma (MM) pathogenesis and is considered a potential drug target. Here we provide evidence of a novel mechanism for PRIMA-1 Met , a small molecule with anti-tumor activity in phase I/II clinical trial, showing that PRIMA-1 Met induces apoptosis in MM cells by suppressing c-Myc and upregulating miRNA-29a. Our study further demonstrates that miRNA-29a functions as a tumor suppressor which targets c-Myc. The baseline expression of miR-29a was significantly lower in MM cell lines and MM patient samples compared to normal hematopoietic cells. In addition, ectopic expression of miRNA-29a or exposure to PRIMA-1 Met reduced cell proliferation and induced apoptosis in MM cells. On the other hand, overexpression of c-Myc at least partially reverted the inhibitory effects of PRIMA-1 Met or miRNA-29a overexpression suggesting the miRNA-29a/c-Myc axis mediates anti-myeloma effects of PRIMA-1 Met . Importantly, intratumor delivery of miRNA-29a mimics induced regression of tumors in mouse xenograft model of MM and this effect synergized with PRIMA-1 Met . Our study indicates that miRNA-29a is a tumor suppressor that plays an important role during PRIMA-1 Met -induced apoptotic signaling by targeting c-Myc and provides the basis for novel therapeutic strategies using miRNA-29a mimics combined with PRIMA-1 Met in MM.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".