Promoter methylation of glutathione S-transferase pi1 and multidrug resistance gene 1 in bronchioloalveolar carcinoma and its correlation with DNA methyltransferase 1 expression.
BACKGROUND
The presence of glutathione S-transferase (GST) pi1 (GSTP1) or multidrug resistance gene 1 (MDR1) promoter methylation in lung cancer was studied for the first time to the authors' knowledge; and, to date, the clinical significance of methylation is not clear. The objective of the current study was to determine the promoter methylation status of GSTP1 and MDR1, which encode GST-pi and P-glycoprotein (Pgp), respectively, in patients with bronchioloalveolar carcinoma (BAC) and to investigate whether methyltransferase 1 (DNMT1)-mediated GSTP1 or MDR1 methylation are responsible for disease progression and prognosis in patients with BAC.


METHODS
Protein expression levels of DNTM1, GST-pi, and Pgp were determined by immunohistochemistry in samples from 36 patients with BAC. Promoter methylation status of the GSTP1 and MDR1 genes was determined by using methylation-specific polymerase chain reaction analysis.


RESULTS
The results demonstrated a significant correlation between the methylation of the GSTP1 or MDR1 promoters and negative expression of their respective proteins in BAC (P < .05). A significant correlation also was demonstrated between GSTP1 methylation and recurrence-free and overall survival of patients with BAC. DNMT1 protein expression levels were correlated with GSTP1 promoter methylation and patient prognosis (P < .05). However, no correlation was observed between DNMT1 expression and MDR1 methylation.


CONCLUSIONS
GSTP1 promoter methylation mediated by DNMT1 may promote BAC progression and could serve as a poor prognostic indicator for patients with this disease. DNMT1 protein expression also may be considered as a prognostic indicator. Methylation of the MDR1 promoter may be mediated through pathways other than DNMT1 in BAC and does not appear to be associated with disease progression or patient prognosis.
Gao
Peng
P
Department of Pathology, School of Medicine, Shandong University, Jinan, People's Republic of China. gaopeng@sdu.edu.cn
Yang
Xi
X
Xue
Yu-Wen
YW
Zhang
Xiao-Fang
XF
Wang
Yan
Y
Liu
Wen-Jun
WJ
Wu
Xiao-Juan
XJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics*; D000328:Adult; D000368:Aged; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D051549:Glutathione S-Transferase pi; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000619380:DNMT1 protein, human