Impact of Ribavirin on Epithlial-Mesenchymal Transition (EMT)
Bibliographic record
Abstract
According to the Canadian Cancer Statistics 2012 annual report, cancer remains a major cause of death, with an estimated 186 400 new cases, and 75 700 deaths. eIF4E is dysregulated in many cancers, including breast cancer. Our lab has considerable preliminary data to suggest that eIF4E, and specifically phosphorylated eIF4E, is involved in the Epithelial-Mesenchymal Transition (EMT) and metastasis. Moreover, Borden, K.L.B., et al., and our lab have recently published that the drug Ribavirin targets eIF4E and inhibits breast cancer cell growth. The main objective of this thesis project is to determine the impact of Ribavirin on EMT. Our data demonstrate that Ribavirin attenuates TGF-β1-induced EMT in NMuMG cells. At the morphological level, cells appear to adopt less of a mesenchymal phenotype, and this is associated with a reduction in expression of the mesenchymal marker, Fibronectin. Importantly, phenotypic changes associated with a TGF-β1-induced EMT could be inhibited by Ribavirin. Specifically, Pro-MMP9 levels are reduced in the presence of Ribavirin, and Ribavirin inhibits wound closure ability by 15%. Ribavirin also attenuates the induction of Snail by TGF-β1 stimulation. Interestingly, Ribavirin also reverts mesenchymal characteristics of mouse MT2186 and human MDA-MB-231 breast cancer lines. As well, Ribavirin inhibits cell invasion by 30% in MT2186 and by 65% in MDA-MB-231 cells. At the molecular level, we provide evidence that Ribavirin may exert its anti-metastatic activity by attenuating the expression of Snail. Snail is a transcription factor and EMT regulator, leading to increased invasiveness and decreased cell proliferation. When we overexpress Snail in MDA-MB-231 cells, this reduces their cell proliferation by 50% and antagonizes Ribavirin's ability to decrease cell growth. Our preliminary data show that Ribavirin can inhibit invasion of MT2186 and MDA-MB-231 cells. However, Ribavirin's ability to inhibit Matrigel invasion is abrogated by overexpressing Snail in MDA-MB-231 cells. In addition, we also provide evidence that Snail is regulated by phosphorylated eIF4E using MEF cells with a non-phosphorylated form of eIF4E, derived from eIF4E Serine 209 Alanine knock-in mice. Together, the results presented in this thesis warrant further investigation into the anti-metastatic activity of Ribavirin in breast cancer. To this end, our lab is planning on testing the efficacy of Ribaivirin in in vivo models of breast cancer metastasis.
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How this classification was reachedexpand
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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".