Abstract 5281: Role of SHP-2 tyrosine phosphatase in colorectal carcinogenesis
Bibliographic record
Abstract
Abstract SHP-2 (Src homology-2 domain-containing phosphatase 2) is a tyrosine phosphatase ubiquitously expressed. Previous work done in SHP-2-/- fibroblasts demonstrated its implication in proliferation and migration as well as in the regulation of many signaling pathways including the Ras-Raf/MEK/ERK, the PI3K/AKT and the Jak/STAT pathways(1). Importantly, gain-of-function mutations were discovered in some colorectal cancers (CRCs)(2). However, the role of SHP-2 in intestinal tumorigenesis has never been investigated. Methods: SHP-2 expression and catalytic activity were analyzed by Western blot, qPCR and immunohistochemistry in human CRC cells and in human tumours from different stages. SHP-2 expression was also analyzed in polyps (adenomas) from mice bearing a mutation in Apc gene (APCMin/+ mice). To elucidate the role of SHP-2, RNA interference was used to specifically downregulate its expression in intestinal epithelial cells transformed or not by the oncogenic form of KRASG12V (IEC/KRas). Proliferation (cell counting), invasion (through Matrigel in Boyden chamber), anchorage-independent growth (soft agar) and tumor formation in nude mice (xenograft assays) were analyzed. Results: 1- SHP-2 mRNA and protein levels were significantly increased in human CRC cells and tumors, especially in adenomas, in comparison to healthy adjacent tissues. 2- Interestingly, polyps from APCMin/+ mice also exhibited marked increase in SHP-2 protein expression in comparison to normal adjacent intestinal epithelium. 3- SHP-2 silencing in IEC/KRAS cells markedly reduced their proliferation rate, their growth in soft agar, their capacity to migrate and invade Matrigel and finally, their capacity to form tumor in vivo, in nude mice. 4- Of note, phosphorylated and activated levels of MEK and ERK kinases were significantly decreased following SHP-2 silencing in IECs particularly in those expressing the mutated form of KRAS. Conclusion: Our data suggest that SHP-2 promotes malignancy of intestinal epithelial cells by sustaining the oncogenic activation of MEK/ERK signalling during intestinal tumorigenesis. (1)Shi ZQ, Lu W, Feng GS., J Biol Chem. 1998 Feb 27;273(9):4904-8. (2)Bentires-Alj M. et al., Cancer Res. 2004 Dec 15;64(24):8816-20. Citation Format: Jessica Gagne Sansfacon, Geneviève Coulombe, Nadia Bourdages, Nathalie Rivard. Role of SHP-2 tyrosine phosphatase in colorectal carcinogenesis. [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 5281. doi:10.1158/1538-7445.AM2014-5281
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".