Aberrant methylation of p57KIP2 gene in lung and breast cancers and malignant mesotheliomas.
The p57KIP2 gene belongs to the Cip/Kip family of CDK inhibitors and has been demonstrated to be a tumor suppressor gene, being inactivated in various types of human cancers. We analyzed the methylation and expression status of p57KIP2 in lung and breast cancers, and in malignant mesotheliomas (MMs). The promoter region of p57KIP2 was determined by methylation-specific PCR (MSP) in samples of lung and breast cancer, and of MM. The expression of the gene in the cell lines was determined by RT-PCR and correlated with the methylation status. Aberrant methylation was detected by MSP in 9 of 27 (33%) and 25 of 78 (32%) lung cancer cell lines and tumors, respectively, 11 of 18 (61%) and 17 of 38 (45%) breast cancer cell lines and tumors, respectively, and 1 of 25 (4%) MM tumors. DNA methylation was detected but rarely in the corresponding non-malignant tissues. In addition, the gene expression was restored in the methylated cell lines following 5-aza-2'-deoxycytidine treatment, confirming that the methylation was indeed responsible for the gene down-regulation. We also examined the relationship between the p57KIP2 methylation status and the clinicopathological features of the primary tumors, and found that there was no relationship between the p57KIP2 methylation status and any of the examined clinicopathological features. In summary, our results demonstrate that p57KIP2 methylation associated with the gene down-regulation is frequently present in lung and breast cancers and plays an important role at the molecular level in the pathogenesis of these cancers.
Kobatake
Takaya
T
Department of Cancer and Thoracic Surgery, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Yano
Masaaki
M
Toyooka
Shinichi
S
Tsukuda
Kazunori
K
Dote
Hideaki
H
Kikuchi
Takefumi
T
Toyota
Minoru
M
Ouchida
Mamoru
M
Aoe
Motoi
M
Date
Hiroshi
H
Pass
Harvey I
HI
Doihara
Hiroyoshi
H
Shimizu
Nobuyoshi
N
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D044584:Carcinoma, Ductal / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins