Inhibition of skeletal metastasis in prostate cancer growth by S-adenosylmethionine (SAM) and methyl binding domain protein 2 (MBD2) knockdown.
Bibliographic record
Abstract
1167 During prostate cancer progression high levels of expression of growth factors and proteases play an important role in tumor growth, invasion and skeletal metastasis; often seen in patients with late stage hormone refractory prostate cancer (HRPC). Urokinase (uPA) plays an important role due to its ability to breakdown extracellular matrix to facilitate tumor invasion and metastasis. We hypothesized that global demethylation, a common epigenomic process, co-activates prometastatic genes in metastatic cancer. Studies carried out in our laboratory have shown the differential expression of uPA in human prostate cancer cells representing early (LnCAP) and late stage (PC-3) disease due to total demethylation of the uPA promoter in PC-3 cells. In the current study, we aim to evaluate the effect of changing the methylation status of the uPA promoter in PC-3 cells and its effect on tumor growth and skeletal metastasis. Towards these goals, PC-3 cells were treated with different doses of the universal methylating agent SAM or transfected with MBD2 antisense oligonucleotides (AS). The inactive homologue of SAM (SAH) and scrambled oligonucleotides (S) were used as control. Treatment of PC-3 cells with SAM or MBD2 knockdown resulted in a dose dependent inhibition in the levels of uPA mRNA expression resulting in a significant decrease in tumor cell invasive capacity. Additional genes involved in tumor progression including MMP-2 and VEGF were also downregulated. No change was observed in the levels of expression of genes known to be partially or fully methylated in HRPC such as GSTP1 and androgen receptor (AR). For in vivo studies, male Balb c nu/nu mice were inoculated with control and experimental cells via subcutaneous route or directly into tibia. Animals receiving cells treated with SAM and AS oligo developed tumors of significantly smaller volume (70%) compared to animals receiving untreated or S oligo transfected cells. In other studies, all animals inoculated with control cells into tibia developed skeletal lesions while animals injected with experimental cells either failed (90%) to develop or developed (10%) lesions of markedly smaller area as determined by X-ray using Faxitron, micro CT and bone histomormphometric analysis. Analysis of affiymetrix microarray of control, SAM and MBD2 treated PC-3 cells showed a significant reduction in the levels of expression of genes coding several factors and their receptors which are involved in tumor growth and skeletal metastasis. Change in the levels of expression of these genes was confirmed and the role of DNA methylation established by bisulfite sequencing. Results from these studies will elucidate the role of DNA demethyaltion in prostate cancer progression and its propensity to metastasize to skeleton which will help in developing new diagnostic, prognostic and therapeutic strategies for patients with HRPC.
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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) | 0.002 | 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 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".