Inhibition of skeletal metastasis in prostate cancer growth by S-adenosylmethionine (SAM) and methyl binding domain protein 2 (MBD2) knockdown.
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».