A JNK-dependent switch determines the oncogenic or tumor suppressor activity of ILKs
Bibliographic record
Abstract
Background: Integrin-linked kinase (ILK) is a potent intracellular kinase involved in the regulation of multiple proliferation and survival kinases, including protein kinase B/Akt, glycogen synthase kinase-3β (GSK3β) and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Evidence suggests ILK is overexpressed and acts oncogenically in a wide variety of primary tumors and genetic models, resulting in induction of tumor cell proliferation, migration, adhesion and angiogenic behaviours. Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. Histological subclassification of RMS yields two major variants, embryonal (ERMS) and alveolar (ARMS). ERMS, as well as multiple other tumors including breast and lung carcinoma, are commonly associated with loss of heterozygosity at 11p15.5, a region harboring the ILK locus. Methods: We utilized cell culture and primary tumors to examine the expression and function of ILK. Results: We demonstrate differential expression of ILK between ERMS and ARMS tumors in vitro and in vivo. RNAi to ILK induces potent gene silencing, with decreases in the phosphorylation of multiple ILK targets. ILK silencing induced inhibition of ARMS, and a contrasting potent stimulation of ERMS cell growth in survival and proliferation assays. These effects were reversed by adenoviral overexpression of ILK in multiple RMS and other tumor cell lines. Moreover, ILK silencing has multiple signaling effects, including induction of cell cycle progression through bmi-1and p16INK4a in ERMS with repression in ARMS, and phosphorylation of c-Jun NH2 terminal kinase (JNK) and c-Jun in ERMS and repression in ARMS cells. Coupling of JNK inhibition with ILK knockdown in ERMS cells inverted the ILK knockdown phenotype, resulting in a significant loss of cell proliferation. Conclusions: Together, these data confirm the oncogenic role of ILK in alveolar rhabdomyosarcoma, and suggest a novel tumor-suppressive role for ILK signaling in embryonal rhabdomyosarcoma, mediated through the novel ILK target axis, JNK-c-Jun.
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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) | 0.005 | 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".