Transformation of normal NIH-3T3 cells into highly oncogenic and invasive cancer cells by MBD2 overexpression
Notice bibliographique
Résumé
3925 Introduction: Cancer cells are hallmarked by global DNA hypomethylation and regional hypermethylation of tumor suppressor genes. The latter has been extensively studied while not much attention has been given to global DNA hypomethylation. MBD2 is the only protein that has been shown to directly remove the methyl group from CG di-nucleotides; though, it has also been reported to be a transcriptional repressor. Inhibition of MBD2 attenuates tumorigenesis, metastasis, and reverses the hypomethylation of metastatic genes in cell culture and in vivo. Additionally, germ line deletion of the mbd2 gene protects mice from intestinal tumors. Therefore, we tested the hypothesis that MBD2 causes oncogenic and metastatic transformation of cells by triggering global hypomethylation. Results: MBD2 and a mutant MBD2 lacking the MBD domain were stably and transiently expressed in mouse fibroblast NIH-3T3 cells. We determined that MBD2 induces global hypomethylation and histone H3 lysine 9 acetylation in an MBD domain dependent manner. Several assays revealed that the MBD2 cell lines, but not the mutant nor the control cell lines, were transformed and highly invasive in cell culture. Only the MBD2 cell lines were highly tumorigenic and invasive when injected into Nude mice while also showing a remarkable ability to invade and degrade bone tissue when injected into the tibia of SCID mice. We also determined that MBD2 is required for maintaining a transformed state triggered by activated HA-RAS in NIH-3T3 cells. MBD2 knockdown in these cells attenuated transformation and increased DNA methylation supporting our hypothesis. To delineate the effects of MBD2 overexpression on specific gene expression, a genomic approach using affymetrix expression arrays was employed. Four hundred and forty four genes were identified to have their mRNA expression altered by MBD2 expression. Genes involved in tumorgenesis, bone degradation, or with no known function that were induced in both MBD2 and HA-Ras expressing cell lines were chosen for further study. Knocking down selected candidate genes9 mRNA in MBD2 overexpressing NIH-3T3 cells resulted in attenuated tumorigenesis while knocking down MBD2 in HA-RAS cells significantly reduced these genes9 expression levels. CHIP assay of the promoter and bisulfite sequencing of the same regions for the candidate genes revealed that MBD2 binds only to regions associated with demethylated DNA and that these regions are associated with H3 lysine 9 acetylation. Summary: Our results support the hypothesis that MBD2, through activation of global cancer pathways, transforms normal fibroblast cells into highly oncogenic, invasive, and metastatic cancer cells; therefore, MBD2 is a novel cancer therapeutic candidate. Supported by a grant from the National Cancer Institute of Canada to MS.
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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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 | 0,001 |
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 ».