Abstract 1305: Alternative splicing of the metabolic regulator Estrogen-Related Receptor alpha (ERRα) in colon carcinogenesis
Notice bibliographique
Résumé
Abstract The nuclear receptor ERRα acts principally in pair with its coactivator PGC-1α as a regulator of metabolic processes particularly in tissues subjected to high-energy demand. Besides its implication in energy metabolism and mitochondrial biogenesis, ERRα was recently associated with tumorigenesis. Increased expression of ERRα was noted in different cancerous tissues as breast, ovary and colon. Also, a new form of ERRα lacking the exon5 (ERRα Δ5) was recently identified and suggested to be a dominant negative of ERRα and interestingly to be differently expressed in normal and cancerous tissues. Since a protumorigenic role is emerging for this metabolic regulator, we investigated the role of ERRα and its spliced form ERRα β5 in colon carcinogenesis. METHODS: shRNA-mediated silencing of ERRα and overexpression of ERRα β5 were performed by lentivirus infection in DLD1 and HCT116 human colon cancer cells. The interaction between both proteins was investigated as well as their respective roles in various tumorigenic processes. RESULTS: Silencing of ERRα by shRNA reduced proliferation of DLD1 and HCT116 cells as measured by growth kinetics and growth assays in soft agar and reduced tumor formation in NUDE mice. Furthermore, FACS-scan analysis revealed that ERRα silencing delays G1-S phase transition in colon cancer cells. Differential expression of a splice variant of ERRα (ERRα Δ5) in cancer vs normal tissues would support the importance of ERRα in colorectal carcinogenesis. This is the case at least for colon tumors as cancerous samples display lower amount of ERRα β5 and higher amount of ERRα compared to adjacent normal tissues. Also, the ERRα β5 expression is surprisingly regulated by proteosomal degradation in normal and colon cancer cell lines and this could explain the low abundance of the ERRα spliced form. Interaction between both variants has been characterized by immunoprecipitation assays, confirming the conserved dimerization potential of ERRα β5 variant with ERRα. Furthermore, luciferase assays revealed that ERRα β5 is transcriptionaly inactive and its expression inhibits the transcriptional activity of ERRα on its target genes, suggesting that this variant acts as a dominant negative for ERRα. Interestingly, the reexpression of ERRα β5 in colon cancer cells reduces soft agar colony formation. CONCLUSION: Strong ERRα expression is associated with cancerous tissues and is required for the intense proliferation of colon cancer cells. Interestingly, the poorly active splice variant ERRα β5 is lost in cancerous colon tissues and has antiproliferative properties when reintroduced in colon cancer cells. Since this splice variant could interact with ERRα and inhibit its activity, ERRα β5 reduction of expression in cancerous tissue could allow ERRα to fully promote colon cancer cell proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1305. doi:1538-7445.AM2012-1305
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,000 |
| 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 ».