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Aberrant expression of N-methylpurine-DNA glycosylase influences patient survival in malignant gliomas.

Liu C, Tu Y, Yuan J, Mao X, He S, Wang L, Fu G, Zong J, Zhang Y - J. Biomed. Biotechnol. (2012)

Bottom Line: MPG gene expression level in glioma tissues was significantly higher than that in non-neoplastic brain tissues (P < 0.001).Moreover, the survival rate of MPG-positive patients was significantly lower than that of MPG-negative patients (P < 0.001).We further confirmed that the over-expression of MPG was a significant and independent prognostic indicator in glioma by multivariate analysis (P < 0.001).

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, The 309th Hospital of PLA, Beijing 100091, China.

ABSTRACT

Aim: To examine the expression of N-methylpurine-DNA glycosylase (MPG) gene and protein in glioma samples with different WHO grades and its association with patients' survival.

Methods: Immunohistochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to investigate the expression of MPG gene and protein in 128 glioma and 10 non-neoplastic brain tissues.

Results: MPG gene expression level in glioma tissues was significantly higher than that in non-neoplastic brain tissues (P < 0.001). Immunohistochemistry also showed that MPG protein was over-expressed in glioma tissues, which was consistent with the resutls of Western blot analysis. Additionally, the expression levels of MPG gene and protein both increase from grade I to grade IV glioma according to the results of real-time PCR, immunohistochemistry and western blot analysis. Moreover, the survival rate of MPG-positive patients was significantly lower than that of MPG-negative patients (P < 0.001). We further confirmed that the over-expression of MPG was a significant and independent prognostic indicator in glioma by multivariate analysis (P < 0.001).

Conclusions: Our data showed the over-expression of MPG gene and protein in human gliomas, and also suggested for the first time that MPG be an unfavorable independent prognostic indicator for glioma patients.

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Related in: MedlinePlus

The schematic diagram of base excision repair (BER) pathway for DNA repair throughout the cell cycle. BER is important for removing damaged bases. BER is initiated by DNA glycosylases (e.g., MPG), which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.
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fig1: The schematic diagram of base excision repair (BER) pathway for DNA repair throughout the cell cycle. BER is important for removing damaged bases. BER is initiated by DNA glycosylases (e.g., MPG), which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.

Mentions: Human gliomas represent 50% to 60% of all intracranial tumors [1]. According to the World Health Organization (WHO) guidelines [2], gliomas are histologically classified into four grades: pilocytic astrocytoma (grade I), low-grade diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma multiforme (GBM, grade IV). Both diagnostic technologies and therapeutic strategies have been greatly advanced, but glioma remains one of the deadliest human cancers. The 5-year survival rates of low-grade (grade I~II) and high-grade (grade III~IV) glioma patients in China are 75.4% and 18.2%, respectively [3]. Especially, the median survival time for patients with GBM is still only 12 months [4]. Indeed, early diagnosis and prolonging survival in glioma patients remains a great challenge for clinicians in the field of neurooncology. There have been several prognostic factors for glioma patients, such as age, preoperative duration of symptoms, Karnofsky performance status (KPS) score, histologic grade, tumor necrosis, surgical resection extent, use of postoperative radiation therapy, and, probably, adjuvant chemotherapy [5]. However, these clinical parameters cannot completely account for the observed variation in survival because of the heterogeneity of glioma patients [6]. Thus, there is an urgent need to further investigate the molecular mechanisms of glioma and to identify the effective prognostic indicators for survival prediction.The DNA-base excision repair (BER) pathway is responsible for the repair of exogenous and endogenous alkylating and oxidative DNA damage, which may lead to carcinogenesis, cell death, and aging if left unrepaired [7]. The schematic diagram of BER pathway is shown as Figure 1. This pathway involves the recognition and removal of damaged bases by a DNA glycosylase, followed by incision of the resulting abasic (AP) site by AP endonuclease, DNA synthesis by polymerase, and strand ligation by DNA ligase [8]. Thus, the BER pathway is an important candidate for intervention into the cellular responses to DNA change. N-methylpurine-DNA glycosylase (MPG) as a DNA repair enzyme is a main component in the BER pathway [9]. In previous study aimed at understanding the significance of initiating lesions removed by the BER pathway, Kaina et al. [10] identified the over-expression of the human MPG in Chinese hamster ovary cells. In the N-alkylpurine repair process, MPG is responsible for the glycolytic removal of the modified base, which leads to the formation of apurinic sites. Although N-alkylpurines have not been found to be directly mutagenic, apurinic sites left by this repair process can block replication and lead to mutation [11]. MPG also participates in the repair of 8-hydroxyguanine and hypoxanthine [12]. Because of the potential role of DNA base lesions in mutagenesis and carcinogenesis, a number of studies have been performed to investigate the association of MPG with various human cancers. Cerda et al. (1998) [13] detected the increased MPG gene and protein expression in the breast cancer cells versus normal breast epithelial cells by northern analysis, southern blots, immunofluorescence, immunohistochemistry, and western blot analysis. In 2001, Sohn et al. [14] reported that the expression of MPG was increased in high-risk HPV-infected cervical neoplasias and the intracellular distribution of MPG protein was altered, suggesting a role of MPG in carcinogenesis. In an effort to improve the efficacy of cancer chemotherapy by intervening into the cellular responses to chemotherapeutic change, many researchers have been interested in the effects of MPG in tumor sensitivity to the clinical chemotherapeutic agents. As their results, MPG-overexpressing ovarian cancer [15], osteosarcoma [16], and breast cancer [17] cells are significantly more sensitive to the clinical chemotherapeutic agents, suggesting that the overexpression of MPG may be a possible gene therapy approach to sensitize tumor cells to the cell-killing effects of chemotherapeutic alkylating agents. The biological mechanism behind the increase of sensitivity to the chemotherapeutic agents in MPG overexpressing cell lines may be that the balance between glycosylase activity, leading to apurinic sites and formation of strand breaks, and subsequent excision repair processes may play an important role in determining cellular cytotoxicity and resistance to alkylating agents [13].


Aberrant expression of N-methylpurine-DNA glycosylase influences patient survival in malignant gliomas.

Liu C, Tu Y, Yuan J, Mao X, He S, Wang L, Fu G, Zong J, Zhang Y - J. Biomed. Biotechnol. (2012)

The schematic diagram of base excision repair (BER) pathway for DNA repair throughout the cell cycle. BER is important for removing damaged bases. BER is initiated by DNA glycosylases (e.g., MPG), which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3303893&req=5

fig1: The schematic diagram of base excision repair (BER) pathway for DNA repair throughout the cell cycle. BER is important for removing damaged bases. BER is initiated by DNA glycosylases (e.g., MPG), which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.
Mentions: Human gliomas represent 50% to 60% of all intracranial tumors [1]. According to the World Health Organization (WHO) guidelines [2], gliomas are histologically classified into four grades: pilocytic astrocytoma (grade I), low-grade diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma multiforme (GBM, grade IV). Both diagnostic technologies and therapeutic strategies have been greatly advanced, but glioma remains one of the deadliest human cancers. The 5-year survival rates of low-grade (grade I~II) and high-grade (grade III~IV) glioma patients in China are 75.4% and 18.2%, respectively [3]. Especially, the median survival time for patients with GBM is still only 12 months [4]. Indeed, early diagnosis and prolonging survival in glioma patients remains a great challenge for clinicians in the field of neurooncology. There have been several prognostic factors for glioma patients, such as age, preoperative duration of symptoms, Karnofsky performance status (KPS) score, histologic grade, tumor necrosis, surgical resection extent, use of postoperative radiation therapy, and, probably, adjuvant chemotherapy [5]. However, these clinical parameters cannot completely account for the observed variation in survival because of the heterogeneity of glioma patients [6]. Thus, there is an urgent need to further investigate the molecular mechanisms of glioma and to identify the effective prognostic indicators for survival prediction.The DNA-base excision repair (BER) pathway is responsible for the repair of exogenous and endogenous alkylating and oxidative DNA damage, which may lead to carcinogenesis, cell death, and aging if left unrepaired [7]. The schematic diagram of BER pathway is shown as Figure 1. This pathway involves the recognition and removal of damaged bases by a DNA glycosylase, followed by incision of the resulting abasic (AP) site by AP endonuclease, DNA synthesis by polymerase, and strand ligation by DNA ligase [8]. Thus, the BER pathway is an important candidate for intervention into the cellular responses to DNA change. N-methylpurine-DNA glycosylase (MPG) as a DNA repair enzyme is a main component in the BER pathway [9]. In previous study aimed at understanding the significance of initiating lesions removed by the BER pathway, Kaina et al. [10] identified the over-expression of the human MPG in Chinese hamster ovary cells. In the N-alkylpurine repair process, MPG is responsible for the glycolytic removal of the modified base, which leads to the formation of apurinic sites. Although N-alkylpurines have not been found to be directly mutagenic, apurinic sites left by this repair process can block replication and lead to mutation [11]. MPG also participates in the repair of 8-hydroxyguanine and hypoxanthine [12]. Because of the potential role of DNA base lesions in mutagenesis and carcinogenesis, a number of studies have been performed to investigate the association of MPG with various human cancers. Cerda et al. (1998) [13] detected the increased MPG gene and protein expression in the breast cancer cells versus normal breast epithelial cells by northern analysis, southern blots, immunofluorescence, immunohistochemistry, and western blot analysis. In 2001, Sohn et al. [14] reported that the expression of MPG was increased in high-risk HPV-infected cervical neoplasias and the intracellular distribution of MPG protein was altered, suggesting a role of MPG in carcinogenesis. In an effort to improve the efficacy of cancer chemotherapy by intervening into the cellular responses to chemotherapeutic change, many researchers have been interested in the effects of MPG in tumor sensitivity to the clinical chemotherapeutic agents. As their results, MPG-overexpressing ovarian cancer [15], osteosarcoma [16], and breast cancer [17] cells are significantly more sensitive to the clinical chemotherapeutic agents, suggesting that the overexpression of MPG may be a possible gene therapy approach to sensitize tumor cells to the cell-killing effects of chemotherapeutic alkylating agents. The biological mechanism behind the increase of sensitivity to the chemotherapeutic agents in MPG overexpressing cell lines may be that the balance between glycosylase activity, leading to apurinic sites and formation of strand breaks, and subsequent excision repair processes may play an important role in determining cellular cytotoxicity and resistance to alkylating agents [13].

Bottom Line: MPG gene expression level in glioma tissues was significantly higher than that in non-neoplastic brain tissues (P < 0.001).Moreover, the survival rate of MPG-positive patients was significantly lower than that of MPG-negative patients (P < 0.001).We further confirmed that the over-expression of MPG was a significant and independent prognostic indicator in glioma by multivariate analysis (P < 0.001).

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, The 309th Hospital of PLA, Beijing 100091, China.

ABSTRACT

Aim: To examine the expression of N-methylpurine-DNA glycosylase (MPG) gene and protein in glioma samples with different WHO grades and its association with patients' survival.

Methods: Immunohistochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to investigate the expression of MPG gene and protein in 128 glioma and 10 non-neoplastic brain tissues.

Results: MPG gene expression level in glioma tissues was significantly higher than that in non-neoplastic brain tissues (P < 0.001). Immunohistochemistry also showed that MPG protein was over-expressed in glioma tissues, which was consistent with the resutls of Western blot analysis. Additionally, the expression levels of MPG gene and protein both increase from grade I to grade IV glioma according to the results of real-time PCR, immunohistochemistry and western blot analysis. Moreover, the survival rate of MPG-positive patients was significantly lower than that of MPG-negative patients (P < 0.001). We further confirmed that the over-expression of MPG was a significant and independent prognostic indicator in glioma by multivariate analysis (P < 0.001).

Conclusions: Our data showed the over-expression of MPG gene and protein in human gliomas, and also suggested for the first time that MPG be an unfavorable independent prognostic indicator for glioma patients.

Show MeSH
Related in: MedlinePlus