期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 8, 页码 3017-3022出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1212333110
关键词
neurotrophin-3; caspase-3; genetic; epigenetic
资金
- Centre National de la Recherche Scientifique
- Institut National de la Sante et de la Recherche Medicale
- Centre Leon Berard
- University of Lyon
- Ligue Contre le Cancer
- Fondation pour la Recherche Medicale
- Institut National du Cancer
- l'Agence Nationale de la Recherche
- Association pour la Recherche contre le Cancer
- Canceropole Rhone Alpes Auvergne
- European Research Council
The TrkC neurotrophin receptor belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase receptor and therefore generally considered to be a protooncogene. We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Furthermore, reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation, as well as in vivo tumor growth. Finally, we provide evidence that a mutation of TrkC detected in a sporadic cancer is a loss-of-proapoptotic function mutation. Together, these data support the conclusion that TrkC is a colorectal cancer tumor suppressor.
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