Hypoxia-Inducible Factor 1 is required for hypoxia-induced resistance to doxorubicin in breast carcinoma cells
Bibliographic record
Abstract
1711 Background: The Hedgehog (HH) pathway signals via Patched (PTCH) and Smoothened (SMO) at the cell surface to GLI in the nucleus. It is known to be required for cell differentiation and organ formation during embryogenesis. Deregulation of HH signaling due to mutations in PTCH or SMO is seen in medulloblastomas and basal cell carcinomas. In a previous microarray-based comparison of expression profiles of 46 synovial sarcoma (SS) samples and 137 samples of 4 other translocation-associated sarcomas (Ewing sarcoma, alveolar rhabdomyosarcoma, desmoplastic small round cell tumor, alveolar soft part sarcoma), we observed features of HH pathway activation in SS, specifically GLI and SMO were significantly overexpressed, as were some downstream targets of GLI such as WIF1 and PDGFRA. We therefore performed a mutational and functional analysis of the HH signaling pathway in SS. Design: Mutational analysis was performed on all coding exons of PTCH and SMO in 40 SS samples and 3 SS cell lines (FUJI, HS-SY-II, SYO-1) by direct sequencing. We also examined the changes in cell growth and in expression of HH target genes and of SUFU, a member of intracellular GLI complex, upon blockade of HH signaling by cyclopamine, a specific inhibitor of SMO, in the 3 SS cell lines. . Result: The mutational analysis revealed no somatic mutations in PTCH and SMO in the 40 SS samples and the 3 SS cell lines. By RT-PCR, all three cell lines expressed GLI, GLI2, GLI3, SUFU, SMO and PTCH. There was a wide range of sensitivity to cyclopamine among 3 cell lines: FUJI cells were most sensitive, with an IC50 (50% reduction in cell counts relative to untreated cells) between 1 uM and 5 uM whereas SYO-1 cells were less sensitive (IC50: 10 uM), and HS-SY-II cells were resistant (IC50>10 uM). We also examined the effect of cyclopamine on genes reported to be transcriptionally up-regulated by HH signaling in other cell types (GLI, PTCH, BCL2, PDGFRA, BMP4, BMP7, CRLF1, SOX9, WIF1, WNT5A). Quantitative RT-PCR assays showed decreases of 80%, 60%, and 30% in the expression levels of GLI, PTCH and BMP4, respectively, relative to untreated cells in the FUJI cell line (p
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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 | 0.001 |
| 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".