Mismatch repair gene promoter methylation and expression in hydatidiform moles.
METHODS
In this study, to investigate the significance of mismatch repair genes (MMR) promoter methylation and expression in the pathogenesis and malignant transformation of hydatidiform moles, we assayed promoter methylation and protein expression of the MMR genes hMLH1 and hMSH2 in gestational trophoblastic diseases (GTDs). DNA was extracted from normal placentas, partial hydatidiform moles, complete hydatidiform moles, and invasive moles, over-digested by methylation-sensitive endonuclease Hpa II, and then the promoters were amplificated by polymerase chain reaction. The protein expression was detected by immunohistochemistry.


RESULTS
In the normal placentas, neither hMLH1 nor hMSH2 promoter methylation was detected. Expression of hMLH1 and hMSH2 in cytotrophoblasts was strongly positive. In partial hydatidiform moles and complete hydatidiform moles, hMLH1 and hMSH2 promoter methylation rates were significantly higher than that of normal placentas (P = 0.000), and the protein expression in cytotrophoblasts was significantly lower (P = 0.000). In the invasive moles, hMLH1 and hMSH2 promoter methylation was not significantly different compared with the partial hydatidiform moles and complete hydatidiform moles (P > 0.05). Expression of hMLH1 in the invasive moles (54.5%, 6 out of 11) was not significantly different compared with the partial hydatidiform moles and complete hydatidiform moles (P > 0.05). But hMSH2 expression in the invasive moles (36.5%, 4 out of 11) was weaker than that in complete hydatidiform moles (P = 0.044). Promoter methylation and less expression of hMSH2 were correlated in complete hydatidiform moles (P = 0.001) and invasive moles (P = 0.039).


CONCLUSIONS
These results indicated that strong expression of hMLH1 and hMSH2 in the cytotrophoblasts of normal placentas may maintain genome stability. Promoter methylation and down-regulation of the expression of hMLH1 and hMSH2 are probably involved in the pathogenesis of hydatidiform moles.
Chen
Huaizeng
H
Central Laboratory, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China.
Ye
Dafeng
D
Xie
Xing
X
Lu
Weiguo
W
Zhu
Changkun
C
Chen
Xiaodong
X
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D005333:Fetus; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005865:Gestational Age; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics* / Q000378:metabolism; D002820:Hydatidiform Mole, Invasive / Q000235:genetics / Q000378:metabolism; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics* / Q000502:physiology; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein