A208 SHP-2 PHOSPHATASE PREVENTS SENESCENCE IN NORMAL AND TUMOR INTESTINAL EPITHELIAL CELLS
Bibliographic record
Abstract
The protein tyrosine phosphatase SHP-2 is known to regulate many cellular functions including growth, differentiation and survival. Interestingly, a gain-of-function mutation (residue E76K) in the gene encoding SHP-2 has been found in some colorectal cancers. Importantly, intestinal epithelial cell (IEC)-specific expression of SHP-2E76K mutant in mice was not sufficient to induce tumorigenesis but markedly promoted tumor growth under the ApcMin/+ background. Conversely, SHP-2 silencing inhibited anchorage-independent growth of human CRC cells (Gagné-Sansfaçon et al., Oncotarget 2016). However, the molecular mechanisms involved in the pro-oncogenic action of SHP-2 remained to be identified. To determine a possible role of the protein tyrosine phosphatase SHP-2 in the development of senescence. Non immortalized human intestinal epithelial cells (HIEC) and human colorectal cancer cells (HCT116) were infected with lentiviruses encoding a shRNA directed against SHP-2. The impact on growth was assessed by BrdU incorporation, SA-β-galactosidase staining and qPCR or immunoblot analyses of regulatory proteins and signaling pathways regulating the cell cycle. SHP-2 deletion was induced ex vivo in intestinal organoids and the impact on organoid development was analyzed. SHP-2 silencing in HIEC changes cell morphology and results in the activation of the Wnt/β-catenin pathway and in the decreased activation of ERK1/2 MAP Kinases. Few days after silencing, the number of cells in S phase is significantly decreased and senescence (SA-β-galactosidase staining) as well as DNA damage (γH2AX) are observed. Western blot and qPCR analyses demonstrate increased expression of the cell cycle inhibitor p27 and increased phosphorylation of p53 on serine 15. Finally, deletion of SHP-2 in enteroids clearly limits their proliferative capacity and development; notably, few days after, organoids loose their integrity and degenerate in contrast to control organoids that continue to develop. In summary, our results suggest that SHP-2 protects intestinal epithelial cells against an oncogenic stress leading to senescence. CIHRCRS
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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 | 0.000 |
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 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".