Kbtbd2 inhibits the cytotoxic activity of immortalized NK cells through down-regulating mTOR signaling in a mouse hepatocellular carcinoma model.
Eur J Immunol
; 48(4): 683-695, 2018 04.
Article
en En
| MEDLINE
| ID: mdl-29331106
ABSTRACT
Natural killer cell (NK cell)-based immunotherapy is a promising therapeutic strategy for hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the regulation of NK cell function in the tumor sites are not completely elucidated. In this study, we identified the enhanced expression of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) in intratumoral NK cells in a mouse HCC implantation model as a negative regulator of NK cells. To investigate this interaction, we used a Tet-on inducible expression system to control Kbtbd2 expression in an immortalized mouse NK cell line KIL C.2. With this approach, we found that overexpression of Kbtbd2 reduced KIL C.2 cell proliferation, decreased expression certain of Ly49 receptor family members, and substantially impaired cytotoxic activity of KIL C.2 cells in vitro. Moreover, phosphorylation of mTOR and its target 4E-binding protein 1 was reduced in Kbtbd2-expressing KIL C.2 cells, along with down-regulated phosphorylation of Erk1/2. Adoptively transferred Kbtbd2-expressing KIL C.2 cells exhibited weaker tumoricidal effect on hepatocellular carcinoma cells in the HCC implantation model, in comparison with transferred control KIL C.2 cells. Taken together, our investigation indicates that Kbtbd2 is an inhibitory molecule for the tumoricidal activity of KIL C.2 cells and perhaps intratumoral NK cells.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Células Asesinas Naturales
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Carcinoma Hepatocelular
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Complejos de Ubiquitina-Proteína Ligasa
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Serina-Treonina Quinasas TOR
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Inmunoterapia
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Neoplasias Hepáticas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Año:
2018
Tipo del documento:
Article