PURPOSE: Because evasion of tumor suppression is a critical step in cancer 
development, cancer cells have developed a variety of mechanisms to circumvent 
the influence of tumor suppressive pathways. Thus, genes that negatively 
regulate tumor suppressors could be considered novel types of oncogenes such as 
Bmi-1 repressing p16Ink4a and inhibiting p53 and were found to be frequently 
up-regulated in a variety of cancers. p38 mitogen-activated protein kinase 
(MAPK), which reportedly plays a crucial role as a tumor suppressor, is 
activated in number of lung adenocarcinomas, which is seemingly at odds with its 
role as a tumor suppressor.
METHODS: We examined 10 lung adenocarcinomas and corresponding normal tissues 
and determined the expression levels of a variety of tumor suppressor proteins 
through real-time polymerase chain reaction and immunohistochemistry and 
measured p38 MAPK activity by immunoblotting or immunohistochemistry analysis. 
In the in vitro cellular model, p38 activation by H-Ras and consequent 
senescence induction was achieved through retro-viral gene transduction. 
Similarly, the suppression of p16Ink4a by Bmi-1 after the introduction of H-Ras 
was achieved through transient transfection with cationic liposome.
RESULTS: We detected several lung adenocarcinomas that were positive for 
activated p38 MAPK but evidenced reduced levels of p16Ink4a expression. The 
suppression of p16Ink4a occurred in parallel with an increase in Bmi-1 and/or 
p16Ink4a promoter hypermethylation. Consistent with these observations, the 
H-Ras-stimulated induction of p16Ink4a was suppressed significantly through the 
coexpression of Bmi-1 in vitro.
DISCUSSION: These results demonstrate that the suppression of p16Ink4a by either 
the induction of Bmi-1 or the hypermethylation of p16Ink4 may be an important 
step in avoiding tumor surveillance by p38 MAPK during the development of lung 
cancer.