miRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc
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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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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) | 0.003 | 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