Methylation Of PTEN And Mismacth Repair Gene Promoters In Gestational Trophoblasts And Trophoblastic Diseases

Introduction DNA methylaion in human genome is the methylation of cytosine residues.lt playes an important role in the development and pathogenesis of tumor. The role of DNA methylation in the pathogenesis of malignant transformation results the aberrant and stable inactivation of suppressor genes and demethylated activation of some oncogenes.in which is referred as epimutation or methylation-associated gene inactivation.lt is an ubiquitous phenomenon that general genome demethylation and local hypermethylation exists in the tumor.The promoter of suppressor genes presents hypomethylation in normal cell, but it often is methylated in tumor.lt is regarded as a main mechanism that inactivation of suppressor genes. The DNA methylation functions in the pathogenesis of tumor.The methylated cytosine is instable and can undergo spontaneous deamination.As a result thymine gives rise to a DNA defect, which induces the reparation system. The situation can be resolved in two ways:the restoration of the wild-type sequence or replacement of G-C base pair by A-T.The early trophoblastic cells show some characteristics of tumor cells,like invasion and transduction via blood stream. But the behavior of trophoblastic cells is benign and self-regulated.lt is suggested that the DNA methylation regulate the expression of some genes in the progress.Gestational trophoblastic diseases(GTDs) is a heterogeneous group of diseases characterized by abnormal proliferation of trophblastic tissues. GTDs include partial and complete2002hydatidiform moles,invasive mole,choriocarcinoma and placental site trophoblastic tumor. Cytogenetic studies reveal that complete moles contain solely paternal contribution to the genome and partial moles contain an excess paternal contribution to the genome.The paternal genome can promote and maintain the placenta proliferation.The mechanism regulating the functional differences between parental genomes was called genomic imprinting,which is believed to play a pivotal role in the pathogenesis of hydatidiform moles. However its precise mechanism remains poorly understood.maybe the DNA methylation plays pivotal role. Hydatidiform moles have a potential to malignant transformation. Similar to other cancers, malignant transformation in GTT is believed to be a mutistep process and involves multiple genetic alterations.GTTs mainly develop from hydatidiform moles.The methylation seems to associated with the pathogenesis of GTTs.PTEN tumor suppressor is a 403-amino acids phosphoprotein/phospholipid dual-specificity phosphatase. Importantly, PTEN possesses lipid phosphatase activity, preferentially dephosphorylating phosphoinositides at the D3 position of the inositol ring. It is the only enzyme known to dephosphorylate the D3 position in inositol phospholipids, suggesting that PTEN may function as a direct antagonist of phosphatidylinositol 3-kinase (PI3-kinase) and phosphatidylinositol 3.4,5-trisphosphate [PtdIns(3,4,5)P3]-dependent signaling. PTEN can downregulate the angiogenesis stimulators including the growth factors, vascular endothelial growth factor and basic fibroblast growth factor, and the induction of matrix remodeling via matrix metalloproteinases. Overexpression of PTEN inhibits cell migration, whereas antisense PTEN enhances migration. Integrin-mediatedcell spreading and the formation of focal adhesions are down-regulated by wild-type PTEN but not by PTEN with an inactive phosphatase domain. PTEN interacts with the focal adhesion kinase FAK and reduces its tyrosine phosphorylation. The PTEN gene is mutated in high-grade gliomas as well as prostate, endometrial, breast, lung, and other tumors. In addition, PTEN is mutated in several rare autosomal dominant cancer52002predisposition syndromes, including Cowden disease, Lhermitte-Duclos disease, and Bannayan-Zonana syndrome.But PTEN mutation is rare in some tumors with lose of PTEN expression.lt seems that the promoter methylation be the main mechanism involved in. DNA mismatch repair (MMR) system ensures the stable replicati...