CIPYP   05508
CENTRO DE INVESTIGACIONES SOBRE PORFIRINAS Y PORFIRIAS
Unidad Ejecutora - UE
artículos
Título:
Homeostatic response under carcinogen withdrawal, heme oxygenase 1 expression and cell cycle association.
Autor/es:
CASTRONUOVO, CYNTHIA; SACCA, PAULA; MEIIS, ROBERTO; CABALLERO, FABIANA; BATLLE, ALCIRA; VAZQUEZ, ELBA
Revista:
BMC Cancer
Editorial:
Biomed Central
Referencias:
Año: 2006 vol. 6 p. 286 - 294
ISSN:
1471-2407
Resumen:
Background: Chronic injury deregulates cellular homeostasis and induces a number of alterations leading
to disruption of cellular processes such as cell cycle checkpoints and apoptosis, driving to carcinogenesis.
The stress protein heme oxygenase-1 (HO-1) catalyzes heme degradation producing biliverdin, iron and
CO. Induction of HO-1 has been suggested to be essential for a controlled cell growth. The aim of this
work was to analyze the in vivo homeostatic response (HR) triggered by the withdrawal of a potent
carcinogen, p-dimethylaminoazobenzene (DAB), after preneoplastic lesions were observed. We analyzed
HO-1 cellular localization and the expression of HO-1, Bcl-2 and cell cycle related proteins under these
conditions comparing them to hepatocellular carcinoma (HC).
Methods: The intoxication protocol was designed based on previous studies demonstrating that
preneoplastic lesions were evident after 89 days of chemical carcinogen administration. Male CF1 mice (n
= 18) were used. HR group received DAB (0.5 % w/w) in the diet for 78 days followed by 11 days of
carcinogen deprivation. The HC group received the carcinogen and control animals the standard diet
during 89 days. The expression of cell cycle related proteins, of Bcl-2 and of HO-1 were analyzed by
western blot. The cellular localization and expression of HO-1 were detected by immnunohistochemistry.
Results: Increased expression of cyclin E/CDK2 was observed in HR, thus implicating cyclin E/CDK2 in
the liver regenerative process. p21cip1/waf1 and Bcl-2 induction in HC was restituted to basal levels in HR.
A similar response profile was found for HO-1 expression levels, showing a lower oxidative status in the
carcinogen-deprived liver. The immunohistochemical studies revealed the presence of macrophages
surrounding foci of necrosis and nodular lesions in HR indicative of an inflammatory response.
Furthermore, regenerative cells displayed changes in type, size and intensity of HO-1 immunostaining.
Conclusion: These results demonstrate that the regenerative capacity of the liver is still observed in the
pre-neoplastic tissue after carcinogen withdrawal suggesting that reversible mechanism/s to compensate
necrosis and to restitute homeostasis are involved.