Abstract A14: DNA alterations to the Cullin-3/Ring box protein-1 E3 ubiquitin ligase complex represent a novel mechanism of NF-κB activation in lung cancer
Bibliographic record
Abstract
Abstract Background: Nuclear factor kappa B (NF-κB) signaling is essential for lung cancer development, and therefore, may serve as a target for intervention. However, the genetic mechanisms responsible for its activation are not fully understood. Kelch-like ECH-associated protein 1 (KEAP1) binds protein substrates to the Cullin-3 (CUL3)/Ring box protein-1 (RBX1) E3 ubiquitin ligase complex where ubiquitination signals substrates for proteosomal degradation. Recently, inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ), an activator of NF-κB, was shown to be a substrate of KEAP1, implicating KEAP1's involvement in regulating NF-κB signaling. Loss of function of KEAP1 leads to IKKβ accumulation and NF-κB activation. We hypothesized that DNA deletions of the other E3 complex components (CUL3 and RBX1) are frequent alterations that disrupt complex function and contribute to NF-κB activation in lung cancer. Methods: We screened DNA copy number profiles of 261 non-small cell lung cancer (NSCLC) tumors for DNA alterations at the KEAP1, CUL3, RBX1, and IKK loci. Profiles were generated by array comparative genomic hybridization on the SMRT array (sub-megabase resolution tiling) platform. We also analyzed mRNA expression of these genes and 9 well annotated NF-κB target genes, using gene expression profiles generated with Agilent gene expression microarrays for a subset (n=48) of the tumors. Results: Our investigation of genetic disruption to the E3 ubiquitin ligase complex components revealed 54% of tumors harbored DNA copy number loss of at least one complex component (KEAP1, CUL3, or RBX1) or gain of IKKβ. Moreover, at the expression level, 81% of tumors analyzed had aberrant expression of one of these genes (underexpression of complex components or overexpression of IKKβ). Interestingly, the copy number alterations identified appeared to segregate with adenocarcinoma (AC) or squamous cell carcinoma (SCC) histology; KEAP1 loss was more prevalent in AC while CUL3 loss and IKKβ gain were more frequent in SCC. When NF-κB target gene expression was analyzed, we observed higher expression of 5/9 genes in tumors with underexpression of an E3 ubiquitin ligase complex component relative to matched non-malignant tissue from the same individual. Conclusions: The presence and strikingly high frequency of genetic disruption and aberrant expression of the E3 ubiquitin ligase complex components (KEAP1, CUL3, and RBX1) revealed in this study provides evidence of its importance in lung cancer. These data suggest that DNA level alterations to this complex may represent a novel mechanism of NF-κB activation in lung cancer. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A14.
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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 | 0.001 | 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) | 0.000 | 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".