Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients.
Epigenetic gene silencing through DNA methylation is one of the important steps in the mechanism underlying tumorigenesis, including in the stomach. Past lifestyle factors of cancer patients, such as intake of vegetables, are very important in affecting gastric carcinogenesis. However, the relationship between DNA methylation and past dietary habits in cancer patients remains largely unknown. The CDX2 homeobox transcription factor plays a key role in intestinal development, but CDX2 is also expressed in most of the intestinal metaplasia and part of the carcinomas of the stomach. We analyzed the methylation status of the CDX2 5' CpG island in gastric cancer cell lines by methylation-specific PCR (MSP), and then CDX2 mRNA was found to be activated after 5-aza-2'-deoxycytidine treatment of the methylation-positive cells. We further examined the methylation status of CDX2 in primary gastric carcinomas by MSP and compared it with the past lifestyle of the patients, including dietary habits. Methylation of CDX2 was found in 20 (34.5%) of the 58 male patients and one (6.7%) of the 15 female patients. Since the methylation frequency was low in the female patients, the analysis was performed only on the male cases. CDX2 methylation was correlated with the decreased intake of green tea and cruciferous vegetables, and also with full or overeating habits. These findings are consistent with epidemiological observations on gastric cancer. We also analyzed the methylation status of p16/INK4a and hMLH1, but their frequencies were not associated with dietary factors or other lifestyle factors. Thus, diet could be an important factor determining the methylation status of genes such as CDX2 and the resultant aberrant expression of genes involved in carcinogenesis.
Yuasa
Yasuhito
Y
Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan. yuasa.monc@tmd.ac.jp
Nagasaki
Hiromi
H
Akiyama
Yoshimitsu
Y
Sakai
Hidekazu
H
Nakajima
Tomoko
T
Ohkura
Yasuo
Y
Takizawa
Touichirou
T
Koike
Morio
M
Tani
Masao
M
Iwai
Takehisa
T
Sugihara
Kenichi
K
Imai
Kazue
K
Nakachi
Kei
K
D048868:Adaptor Proteins, Signal Transducing; D000071616:CDX2 Transcription Factor; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D004032:Diet; D044127:Epigenesis, Genetic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000070957:MutL Protein Homolog 1