Abstract 1140: Par-4 mediates EMT in response to TGF-β stimulation
Bibliographic record
Abstract
Abstract Endometrial cancer is the most common cancer affecting the female genital tract; this disease also stands as the fourth most frequent cancer affecting occidental women. Endometrial cancer is generally well manageable; however, the high metastatic potential of endometrial tumors represents one of the major hurdles in the treatment of this disease. The epithelial to mesenchymal transition (EMT) has been considered for a long time as a central mechanism by which cancer cells acquire invasive abilities necessary for metastasis formation. Multiple regulatory networks dictate this complex process; however TGF-β has been shown to be one of the most important inductor of EMT in cancer cells. Still, the process by which TGF-β induces this transition has yet to be fully understood. Our study demonstrates that TGF-β upregulates the expression of Par-4, a tumor suppressor protein concomitantly with the onset of EMT. Four uterine cell lines (Hec-1-a, KLE, HeLa, HIESC), one ovarian cell line (SKOV-3) and one breast cell line (MCF7) were used in this study. We first investigated the effect of exogenous TGF-β treatment on these cell lines to determine its effect on Par-4 expression. We've observed that TGF-β increased Par-4 levels in every cell lines. Preliminary analysis determined that this regulation was made through both Smad4 and p65, which was confirmed by the use of siRNA. We've also demonstrated that this regulation was made at the transcriptional level by RT-qPCR. We then sought to confirm the effect of TGF-β on our cell lines and its effect on EMT induction. Our experiments demonstrated that TGF-β promotes EMT as suggested by the upregulation of multiple EMT markers. Transfections using Par-4 expression plasmids induced similar changes, indicating the involvement of Par-4 in TGF-β mediated EMT induction. We then proceeded to assess the effect of Par-4 knockdown concurrent with exogenous TGF-β stimulation. This experiment revealed that Par-4 knockdown reduced the ability of TGF-β to induce Snail expression, further demonstrating the importance of Par-4 in the process of TGF-β mediated EMT. To conclude the study, we sought to understand the effect of XIAP in this process. Our experiments uncovered that XIAP regulates full length Par-4 levels through the inhibition of its caspase-mediated cleavage. Furthermore, the inhibition of XIAP by siRNAs, and thus of Par-4 cleavage, resulted in the reduction of Par-4 EMT inducing capabilities. In conclusion, our study proposes a novel function of Par-4 as an inductor of EMT in multiple cell lines. Citation Format: François Fabi, Parvesh Chaudhry, Mohan Singh, Eric Asselin. Par-4 mediates EMT in response to TGF-β stimulation. [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 1140. doi:10.1158/1538-7445.AM2014-1140
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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 | 0.003 | 0.003 |
| 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 | 0.000 |
| 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".