期刊
CANCER RESEARCH
卷 80, 期 16, 页码 3236-3250出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-19-0855
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资金
- Association Sauvons Laura
- Association Dimitri Bessieres
- Agence Nationale pour la Recherche (ANR Jeunes Chercheurs, Jeunes Chercheuses, GLIOMIRSTEM project)
- Fondation de France
- Association pour la Recherche sur le Cancer
- INCA PLBIO
- ITMO CANCER plan cancer
- Association pour le developpement de la Recherche sur les tumeurs urologiques, cerebrales et pulmonaires (ADeRTU)
- INSERM
- CNRS
- UNSA
- UCA
- Conseil departemental 06
- Canceropole PACA
There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated toggle switch that promotes pluripotency marker expression and stem-like features in GBM cells. Significance: This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency.
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