Abstract 4372: MiR-449a promotes breast cancer progression by activating the NF-κB pathway
Bibliographic record
Abstract
Abstract INTRODUCTION MicroRNAs (miRs) have been implicated in various human malignancies and are being developed as diagnostic, predictive, and prognostic biomarkers. Our previous global profiling studies found miR-449a to be over-expressed in archival lymph node-negative invasive ductal breast carcinoma samples (n=74) when compared to normal tissues. Furthermore, miR-449a expression level was significantly associated with relapse. The mechanism(s) by which miR-449a functions remains unknown, and the aim of the current study was therefore to elucidate the roles and mRNA targets of miR-449a in breast cancer. MATERIAL AND METHODS MiR-449a expression was evaluated in six human breast cancer cell lines (T47D, MDA-MB-468, MDA-MB-231, MCF-7, MDA-MB-453, and ZR75-1). Three of these cell lines, T47D, MMDA-MB-468, and MDA-MB-231, were selected and used to assess the biological effects of miR-449a on cell viability, clonogenicity, cell migration, and invasion. Downstream target genes were identified by combining in silico miRWalk prediction and cell line/patient sample microarray data. Targets were validated using qRT-PCR and luciferase reporter assays. RESULTS Consistent with our global profiling work, several (4/6) of the tested breast cancer cell lines over-expressed miR-449a. CDC20B, the miR-449a host gene and an essential regulator of cell division, was also over-expressed. Knockdown of miR-449a resulted in significantly decreased cell viability, clonogenic survival, migration, and invasion. MiR-449a candidate targets were then identified by integrating in silico prediction algorithms, cell line mRNA expression profiling (Affymetrix Human Genome U133 Plus 2.0), and clinical specimen mRNA expression data. Two genes, CRIP2 (Cysteine rich protein 2, a transcription factor) and PRKAG1 (Protein Kinase, AMP-Activated, Gamma 1 Non-Catalytic), were verified as miR-449a targets using qRT-PCR. Moreover, direct interactions between miR-449a and the 3′-UTRs of both CRIP2 and PRKAG1 were confirmed using luciferase reporter assays. Inhibition of CRIP2 by miR-449a allowed for NF-κB-induced transcription of survival, proliferation, and growth-related genes, providing further evidence for the role of miR-449a in breast cancer progression. CONCLUSIONS MiR-449a is over-expressed in breast cancer cells, promoting cellular proliferation, migration, and invasion. One mechanism by which miR-449a functions is to down-regulate CRIP2, leading to NF-kB activation and possible cancer progression. Further investigations into gene regulation by miR-449a may reveal other promising targets for the management of breast cancer. Citation Format: Wei Shi, Matthew Lee, Ryunosuke Kogo, Jeff Bruce, Christine How, Kenneth W. Yip, Fei-Fei Liu. MiR-449a promotes breast cancer progression by activating the NF-κB pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4372. doi:10.1158/1538-7445.AM2014-4372
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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) | 0.005 | 0.002 |
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".