Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-κB.
Mol Cell Biol
; 36(12): 1776-92, 2016 06 15.
Article
em En
| MEDLINE
| ID: mdl-27090639
ABSTRACT
We and others have shown that the cystatin E/M gene is inactivated in primary human tumors, pointing to its role as a tumor suppressor gene. However, the molecular mechanism of tumor suppression is not yet understood. Using plasmid-directed cystatin E/M gene overexpression, a lentivirus-mediated tetracycline-inducible vector system, and human papillomavirus 16 (HPV 16) E6 and E7 gene-immortalized normal human epidermal keratinocytes, we demonstrated intracellular and non-cell-autonomous apoptotic growth inhibition of tumor cell lines and that growth inhibition is associated with cytoplasmic retention of NF-κB. We further demonstrated decreased phosphorylation of IκB kinase (IKKß) and IκBα in the presence of tumor necrosis factor alpha (TNF-α), confirming the role of cystatin E/M in the regulation of the NF-κB signaling pathway. Growth suppression of nude mouse xenograft tumors carrying a tetracycline-inducible vector system was observed with the addition of doxycycline in drinking water, confirming that the cystatin E/M gene is a tumor suppressor gene. Finally, immunohistochemical analyses of cervical carcinoma in situ and primary tumors have shown a statistically significant inverse relationship between the expression of cystatin E/M and cathepsin L and a direct relationship between the loss of cystatin E/M expression and nuclear expression of NF-κB. We therefore propose that the cystatin E/M suppressor gene plays an important role in the regulation of NF-κB.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias do Colo do Útero
/
NF-kappa B
/
Fator de Necrose Tumoral alfa
/
Proteínas I-kappa B
/
Citoplasma
/
Cistatina M
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article