Abstract 1444: Stathmin suppression influences ROCK signaling and reduces cell invasion and metastasis in neuroblastoma
Bibliographic record
Abstract
Abstract Neuroblastoma is a highly metastatic childhood cancer of the sympathetic nervous system. Stathmin is a microtubule destabilizing protein highly expressed in neuroblastoma though studies addressing its functional role in this malignancy have been limited. The Rho- Rho-associated coiled-coil forming kinase (Rho-ROCK) signaling pathway has been implicated in metastasis through its regulation of the cell cytoskeleton namely the actin remodeling proteins, cofilin and myosin light chain (MLC), and microtubule dynamics. The aims of this study were to determine whether stathmin influenced the Rho-ROCK signaling pathway and metastasis in neuroblastoma. Methods: SiRNA-mediated stathmin suppression was confirmed in 2 independent neuroblastoma cell lines, BE(2)-C and SY5Y, by qPCR and western blot. The cell cytoskeleton of siRNA-transfected cells was visualized by staining with phalloidin (actin filaments) and β-tubulin (microtubules) and tubulin polymer levels were examined by western blot. The expression of cofilin and MLC in siRNA-transfected cells, following treatment with the ROCK inhibitor Y-27632, were analyzed by western blot. SiRNA-transfected cells were subjected to chemotaxis transwell migration and invasion assays. To assess stathmin's role in neuroblastoma metastasis, two million control or stathmin shRNA/luciferase-expressing neuroblastoma cells [SK-N-BE(2)/TGL] were injected into the left adrenal fat pad of 8 week old SCID-Beige mice. Tumor growth was monitored weekly using the Xenogen IVIS System. Mice were sacrificed when primary tumors reached 1500mm3, 38 days post-injection or upon health decline. Ex vivo imaging and IHC confirmed neuroblastoma cells in the lungs of mice. Results: SiRNA-mediated stathmin suppression significantly reduced neuroblastoma cell migration by 44-47% [SY5Y cells 44% reduction (p<0.05) and BE(2)C cells 47% reduction (p<0.001)] and invasion through an extra-cellular matrix by 55-62% [SY5Y cells 55% reduction (p<0.05) and BE(2)C cells 62% reduction (p<0.05)]. Stathmin suppression also altered neuroblastoma cell morphology and this was associated with changes in the cytoskeleton including increased tubulin polymer levels and the phosphorylation of cofilin and MLC. Treatment of stathmin-suppressed neuroblastoma cells with Y-27632 ablated MLC phosphorylation, and returned the level of cofilin phosphorylation and cell invasion back to that of untreated control cells. This highlights a novel link between stathmin expression and ROCK signaling. In vivo, shRNA-mediated stathmin suppression did not influence neuroblastoma tumor growth. In contrast, stathmin suppression significantly reduced metastatic neuroblastoma tumor burden in the lungs by 71% (p<0.01) compared to controls. Conclusion: Stathmin is a novel mediator of metastasis in neuroblastoma and potential therapeutic target for this deadly disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1444. doi:1538-7445.AM2012-1444
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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) | 0.003 | 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".