PTEN Expression And Regulation In Gliomas

Glioma is the most common subtype of primary brain tumors. The development and progression of glioma is a complex multistep process involving numerous molecular events, such as activation of oncogenes and inactivation of suppressor genes. PTEN gene is a tumor suppressor gene, which was first identified in 1997 and located on 10q23.3. It is reported that PTEN mutations and deletions are present in about 27% to 44% of glioblastomas , which shows that PTEN might be a crucial molecular event in glioma tumorigenesis , especially in the process of malignant transformation. Then, study on the expression and regulation of PTEN in gliomas will help to further understand the function of PTEN in glioma.TGF- is a multifunctional cytokine and a double-edged sword in tumorigenesis. At early stage of tumorigenesis , it suppresses tumor outgrowth. As the tumor progresses , however, overexpression of TGF- enhances invasion and metastasis of tumor cells . TGF- 1 treatment leads to the downregulation of PTEN mRNA in some tumor cell lines.To investigate the mechanism of PTEN in human gliomas , a study was performed.1. The expression of TGF-1, P53 and PTEN in 92 specimens of human glioma was detected by immunohistochemistry. We found that the expression of TGF- 1 and P53 had significantly positive correlation with pathological grade(P < 0.05 , P < 0.01). The expression of PTEN had significantly negative correlation with pathological grade(P < 0.05). The significant relationship was seen between the expression of TGF- 1 and p53 in specimens(r=0.231, P<0.05).The cases with P53 expression and the lossof PTEN expression showed poor prognosis(P<0.05, P<0.05) .2. Semi-nested PCR, DHPLC and DMA Sequencing Analysis were conducted in the glioma tissues in order to evaluate the mutation of PTEN in gliomas. 58%(29/50) of the tumors showed a negative expression of PTEN in which 62.1% are low-grade. PTEN mutation in exon 5, 6 were not found , which indicated the abnormity of PTEN transcription regulation in glioma .3. Cell culture , RT-PCR, Westernblot were applied to get more information about how TGF- 1 repressed the transactivation of PTEN gene expression in LN751 cell line. TGF- 1 could restrain expression of PTEN in LN751 cell line and TGF 1 -mediated inhibition of PTEN expression was significantly correlated with ERK1/2 phosphorylation. Blocking the MEK1/ERK signal pathway by PD98059 abolished the repression of PTEN expression by TGF- I.Then, it is implied that there are correlation between ERK1/2 phosphorylation and TGF- 1 repressing transactivation of PTEN gene expression.Our results suggest that:1 .abnormal expression of TGF- 1, PTEN, P53 might be molecular events in the initiation and development of glioma.2. P53 expression and the loss of PTEN expression were considered to be valuable factors in evaluating the glioma malignancy and the prognosis of patients.3.TGF 1 could inhibit the mRNA expression of PTEN in LN751 cell line , which might be correlated with ERK1/2 phosphorylation.4.The abnormity of PTEN transcription regulation in glioma might be result in the down-expression of PTEN.