GRIM-19和STAT3基因在脑胶质瘤中的表达及意义
摘要
背景和目的
脑胶质瘤是颅内发生率最高的肿瘤,其大多呈浸润式生长,目前靠外科手术切除为主,术后辅以放疗、化疗、基因治疗、免疫治疗等治疗手段。尽管治疗手段都有较大进步,由于恶性脑胶质瘤具有生长迅速,侵袭性强,术后易复发等特点,其预后仍不尽人意。尤其是多形性胶质母细胞瘤病人的中位存活时间仅仅12～15个月。故对于脑恶性胶质瘤的发生、恶性进展和治疗的研究是医学及其相关研究领域研究的重要课题之一。近年来随着分子生物学在肿瘤研究的发展,对脑胶质瘤研究的相关分子机制和凋亡的研究已经较为深入,但胶质瘤的发生机制仍不清楚。
干扰素-维甲酸联合诱导细胞死亡相关基因GRIM-19(Gene associated with retinoid-IFN-induced mortality)是在研究干扰素β(interferon-β;IFN-β)和全反式维甲酸(all.trans-retinoic acid,RA)诱导细胞凋亡过程中用反义敲除技术筛选出的一个新基因。GRIM-19不属于现在已知的任何凋亡基因如Bel-2.death recepor和caspase家族。目前认为,GRIM-19参与细胞的增殖、凋亡的调控过程,其表达降低或位点突变可以导致细胞的异常增殖和恶性转化。转录信号转导子与激活子3(signal transducers and activators of transcription3,STAT3)是一类近年发现的癌基因,STAT3信号转导通路作为信号转导和转录激活因子家族的重要成员,其持续激活与肿瘤的发生、发展密切相关。人们发现STAT3的组成性激活对肿瘤细胞的存活、增殖、血管发生、侵袭和转移、免疫逃脱都发挥着重要的作用。体内外抑制某些肿瘤细胞中STAT3信号通路,可抑制细胞的增殖和存活,并诱导细胞凋亡。GRIM-19参与调控该家族的STAT3的活性,GRIM-19被认为是STAT3表达和激活的新的负调节子。GRIM-19在脑胶质瘤中的研究较少,GRIM-19与STAT3在脑胶质瘤中联合检测未见相关文献报道。本研究通过采用RT-PCR技术检测GRIM-19mRNA与STAT3mRNA在脑胶质瘤组织和非瘤组织中的表达来研究其在脑胶质瘤中发生、发展中的作用,为临床人脑胶质瘤的治疗提供新的思路。
材料和方法
45例胶质瘤的标本取自2010年9月-2012年5月郑州大学第二附属医院神经外科。所有胶质瘤标本取自肿瘤实质部分,不包含中心坏死及肿瘤边界区,取材后均经过病理专家的诊断证实。所有病例均为首次发病,术前均未行放、化疗。其中,男28例,女17例,年龄在2～73岁,平均37.23±16.35岁。标本取出后迅速存放于液氮内,后转存于-80℃冰箱内。严格按照2007年WHO中枢神经系统肿瘤的分级标准进行分级,其中Ⅰ级5例,Ⅱ级18例,Ⅲ级12例,Ⅳ级10例。Ⅱ～Ⅱ级为低度恶性组,23例；Ⅲ～Ⅳ级为高度恶性组,22例。此外,另取13例脑外伤或脑出血患者的非瘤脑组织标本作为对照组。采用RT-PCR技术检测GRIM-19、STAT3基因mRNA在45例胶质瘤组织和13例非瘤脑组织中的表达量,并利用SPSS17.0软件进行统计学分析,检验水准为a=0.05。
结果
1. GRIM-19mRNA在不同级别脑胶质瘤中的表达情况
GRIM-19mRNA在胶质瘤组织标本呈现低表达,而在非瘤脑组织中出现高表达。GRIM-19mRNA在非瘤脑组织、脑胶质瘤组织、低度恶性胶质瘤组、高度恶性胶质瘤组中的表达量分别为1.091±0.025、0.923±0.076、0.986±0.040、0.856±0.040。经过统计分析显示,非瘤脑组织和脑胶质瘤组织之间、非瘤脑组织、低度恶性胶质瘤组和高度恶性胶质瘤组两两之间均具有显著差异(P<0.05)。
2. STAT3mRNA在不同级别脑胶质瘤中的表达情况
STAT3mRNA在胶质瘤组织标本呈现高表达,而在非瘤脑组织中出现低表达。STAT3mRNA在非瘤脑组织、脑胶质瘤组织、低度恶性胶质瘤组、高度恶性胶质瘤组中的表达量分别为0.671±0.020、0.818±0.049、0.786±0.030、0.843±0.041。经统计学分析显示,非瘤脑组织和脑胶质瘤组织之间、非瘤脑组织、低度恶性胶质瘤组和高度恶性胶质瘤组两两之间均具有显著差异(P<0.05)。
3.GRIM-19、STAT3基因之间的相关性
GRIM-19mRNA和STAT3mRNA在同一脑胶质瘤组织中的表达量,经统计学分析,二者为负相关,二者的表达趋于反向,Pearson相关性r=-0.618,P<0.05,具有统计学的意义。
结论
1.GRIM-19基因在脑胶质瘤中的mRNA表达相对于非瘤脑组织明显减弱,且随着胶质瘤病理级别的升高,其表达量逐渐降低。
2.STAT3基因在脑胶质瘤中的mRNA表达相对于非瘤脑组织明显增强,且随着胶质瘤病理级别的升高,其表达量逐渐升高。
3.GRIM-19、STAT3基因在脑胶质瘤中的表达呈负相关。GRIM-19、STAT3基因有望成为脑胶质瘤基因诊断与治疗的靶点。
Background and Purpose
Glioma is the most easily approached tumor in the encephalic.It almost exacerbates as infiltrating type. So far it mainly depends on surgery cutting to treat and it should be maintained with the help of radiotherapy,chemotherapy, genetherepy, immuno therapy and so on after the surgery. Although there has been great improvement in treatment methods, malignancy features by rapid growth,strong invasion and easy recurrence. So it is not satisfying after surgery. The median survival time of people who are afflicted with GBM(glioblastoma multiforme) is merely12-15months. Thereafter,the study of the beginning, deteriorating, and treatment is an important subject in the medical and some relative areas, In recent years, with the development of the molecular biology in the cancer research,the study of molecular mechanism and withering had been further explored,but the occurrence mechanism of glioma is not clear.
GRIM-19(Gene associated with retinoid-IFN-induced mortality) which is induced by interferon/retinoic acid and can make cells deteriorate is a new gene chosen in the study of interferon-β; IFN-β and all-trans-retinoic acid, RA inducing cells to apoptosis by the way of delating opposite elements. GRIM-19is not belonged to any of the already known apoptosis gene.eg:Bcl-2,death recepor and caspase family. So far as concerned, GRIM-19participates in the process of cell proliferation and repoptosis,and the reduction of expression and site mutation may lead to the cell proliferation and vicious transformation. STAT3signal transduction pathway is a recently discovered cancer gene and it works as an important member in the gene family of transducing and transcribing the activator. The constant activating associates closely to the beginning and developing of tumor. It is discovered that the constitutive activation of STAT3plays a important role in the survival, proliferation, vasculogenesis, invasion and transferring, Immune escape.The suppression of STAT3signal Signal transduction pathway in and out of the body can restrain the cell proliferation and survival as well as inducing cells to apoptosis. GRIM-19is considered as a new negative regulator to express and activate STAT3. The study of GRIM-19in glioma is rare, and we can see no relative papers reporting GRIM-19and STAT3together. This research is to study its function in the beginning and developing of the glioma by the way of RT-PCR technical testing for the expression of GRIM-19mRNA and STAT3mRNA in the glioma tissues and non-neoplastic brain tissue so as to provide new idea in the clinic treatment for glioma.
Materials and Methods
45samples is got from the neurosurgery of the second Affiliated Hospital of Zhengzhou University. All the tumor samples are got from the parenchyma of the tumor, not including the central necrosis and Tumor border area,and they are through the diagnosis of the pathologist.All the samples are attacked for the first time,and they are not treated with radiotherapy and chemotherapy. Among them,there are28men and17women whose age is2-73years old,and the average age is37.23±16.35years old. The samples are stored in the liquid nitrogen after they are obtained and then transferred into the refrigerator of-80℃. They are strictly classified according to the the classification standard of the central nervous system tumors which is released by WHO in2007. Among them,there are5Ⅰ,18Ⅱ,12；,10Ⅳ. Ⅰ～Ⅱ belong to the lower malignancy group, the amount is23; Ⅲ-Ⅳ belong to the higher malignancy group,number22.Besides,13normal cerebral tissue samples of brain injury or cerebral hemorrhage patients are picked as normal control.After the RT-PCR test for the expression of GRIM-19mRNA、 STAT3gene mRNA in the45glioma tissues and the13tumor tissues. The result were analyzed with the statistics software of SPSS17.0. Probabiilty values a=0.05were considered statistically significant.
Results
1. The expression of GRIM-19mRNA in different grade glioma
GRIM-19mRNA presents low expression in glioma tissue specimens; high expression in the non-tumor brain tissue. The expression of GRIM-19mRNA in the non-tumor brain tissue,glioma tissue, low-grade malignant tumor tissues,highly malignant glioma group is respectively1.091、0.025、0.923、.076、0.986±040、0.856±0.040. The differences were significant between non-tumor brain tissue and glioma tissues, as well as between any two of the non-tumor brain tissue, low-grade malignant gliomas and high-grade gliomas.(P<0.05)
2.The expression in different grade glioma
STAT3mRNA presents high expression in glioma tissue specimens; low expression in the non-tumor brain tissue. The expression of STAT3mRNA in the non-tumor brain tissue,glioma tissue, low-grade malignant tumor tissues,highly malignant glioma group is respectively:0.671±0.020、0.818±0.049、0.786±0.030、0.843±0.041. The differences were significant between non-tumor brain tissue and glioma tissues, as well as between any two of the non-tumor brain tissue, low-grade malignant gliomas and high-grade gliomas.(P<0.05)
3.The relevancy between GRIM-19and STAT3
According to statistics,the expression of GRIM-19mRNA and STAT3mRNA is negative correlation,their expression is tend to opposite sides. The pearson relation is r=-0.618, P<0.05, and it makes sense in statistics.
Conclusions
1.The mRNA expression of GRIM-19gene in the glioma is obviously weakened which is compared to non-tumor brain tissue.As the pathological grade rises, the expression reduces gradually.
2.The mRNA expression of STAT3gene in the glioma is obviously strengthened which is compared to non-tumor brain tissue. As the pathological grade rises, the expression promotes gradually.
3.The expression of GRIM-19and STAT3presents negative correlation. GRIM-19and STAT3are expected to become the target spot in the diagnosis and treatment of glioma gene.
脑胶质瘤是颅内发生率最高的肿瘤,其大多呈浸润式生长,目前靠外科手术切除为主,术后辅以放疗、化疗、基因治疗、免疫治疗等治疗手段。尽管治疗手段都有较大进步,由于恶性脑胶质瘤具有生长迅速,侵袭性强,术后易复发等特点,其预后仍不尽人意。尤其是多形性胶质母细胞瘤病人的中位存活时间仅仅12～15个月。故对于脑恶性胶质瘤的发生、恶性进展和治疗的研究是医学及其相关研究领域研究的重要课题之一。近年来随着分子生物学在肿瘤研究的发展,对脑胶质瘤研究的相关分子机制和凋亡的研究已经较为深入,但胶质瘤的发生机制仍不清楚。
干扰素-维甲酸联合诱导细胞死亡相关基因GRIM-19(Gene associated with retinoid-IFN-induced mortality)是在研究干扰素β(interferon-β;IFN-β)和全反式维甲酸(all.trans-retinoic acid,RA)诱导细胞凋亡过程中用反义敲除技术筛选出的一个新基因。GRIM-19不属于现在已知的任何凋亡基因如Bel-2.death recepor和caspase家族。目前认为,GRIM-19参与细胞的增殖、凋亡的调控过程,其表达降低或位点突变可以导致细胞的异常增殖和恶性转化。转录信号转导子与激活子3(signal transducers and activators of transcription3,STAT3)是一类近年发现的癌基因,STAT3信号转导通路作为信号转导和转录激活因子家族的重要成员,其持续激活与肿瘤的发生、发展密切相关。人们发现STAT3的组成性激活对肿瘤细胞的存活、增殖、血管发生、侵袭和转移、免疫逃脱都发挥着重要的作用。体内外抑制某些肿瘤细胞中STAT3信号通路,可抑制细胞的增殖和存活,并诱导细胞凋亡。GRIM-19参与调控该家族的STAT3的活性,GRIM-19被认为是STAT3表达和激活的新的负调节子。GRIM-19在脑胶质瘤中的研究较少,GRIM-19与STAT3在脑胶质瘤中联合检测未见相关文献报道。本研究通过采用RT-PCR技术检测GRIM-19mRNA与STAT3mRNA在脑胶质瘤组织和非瘤组织中的表达来研究其在脑胶质瘤中发生、发展中的作用,为临床人脑胶质瘤的治疗提供新的思路。
材料和方法
45例胶质瘤的标本取自2010年9月-2012年5月郑州大学第二附属医院神经外科。所有胶质瘤标本取自肿瘤实质部分,不包含中心坏死及肿瘤边界区,取材后均经过病理专家的诊断证实。所有病例均为首次发病,术前均未行放、化疗。其中,男28例,女17例,年龄在2～73岁,平均37.23±16.35岁。标本取出后迅速存放于液氮内,后转存于-80℃冰箱内。严格按照2007年WHO中枢神经系统肿瘤的分级标准进行分级,其中Ⅰ级5例,Ⅱ级18例,Ⅲ级12例,Ⅳ级10例。Ⅱ～Ⅱ级为低度恶性组,23例；Ⅲ～Ⅳ级为高度恶性组,22例。此外,另取13例脑外伤或脑出血患者的非瘤脑组织标本作为对照组。采用RT-PCR技术检测GRIM-19、STAT3基因mRNA在45例胶质瘤组织和13例非瘤脑组织中的表达量,并利用SPSS17.0软件进行统计学分析,检验水准为a=0.05。
结果
1. GRIM-19mRNA在不同级别脑胶质瘤中的表达情况
GRIM-19mRNA在胶质瘤组织标本呈现低表达,而在非瘤脑组织中出现高表达。GRIM-19mRNA在非瘤脑组织、脑胶质瘤组织、低度恶性胶质瘤组、高度恶性胶质瘤组中的表达量分别为1.091±0.025、0.923±0.076、0.986±0.040、0.856±0.040。经过统计分析显示,非瘤脑组织和脑胶质瘤组织之间、非瘤脑组织、低度恶性胶质瘤组和高度恶性胶质瘤组两两之间均具有显著差异(P<0.05)。
2. STAT3mRNA在不同级别脑胶质瘤中的表达情况
STAT3mRNA在胶质瘤组织标本呈现高表达,而在非瘤脑组织中出现低表达。STAT3mRNA在非瘤脑组织、脑胶质瘤组织、低度恶性胶质瘤组、高度恶性胶质瘤组中的表达量分别为0.671±0.020、0.818±0.049、0.786±0.030、0.843±0.041。经统计学分析显示,非瘤脑组织和脑胶质瘤组织之间、非瘤脑组织、低度恶性胶质瘤组和高度恶性胶质瘤组两两之间均具有显著差异(P<0.05)。
3.GRIM-19、STAT3基因之间的相关性
GRIM-19mRNA和STAT3mRNA在同一脑胶质瘤组织中的表达量,经统计学分析,二者为负相关,二者的表达趋于反向,Pearson相关性r=-0.618,P<0.05,具有统计学的意义。
结论
1.GRIM-19基因在脑胶质瘤中的mRNA表达相对于非瘤脑组织明显减弱,且随着胶质瘤病理级别的升高,其表达量逐渐降低。
2.STAT3基因在脑胶质瘤中的mRNA表达相对于非瘤脑组织明显增强,且随着胶质瘤病理级别的升高,其表达量逐渐升高。
3.GRIM-19、STAT3基因在脑胶质瘤中的表达呈负相关。GRIM-19、STAT3基因有望成为脑胶质瘤基因诊断与治疗的靶点。
Background and Purpose
Glioma is the most easily approached tumor in the encephalic.It almost exacerbates as infiltrating type. So far it mainly depends on surgery cutting to treat and it should be maintained with the help of radiotherapy,chemotherapy, genetherepy, immuno therapy and so on after the surgery. Although there has been great improvement in treatment methods, malignancy features by rapid growth,strong invasion and easy recurrence. So it is not satisfying after surgery. The median survival time of people who are afflicted with GBM(glioblastoma multiforme) is merely12-15months. Thereafter,the study of the beginning, deteriorating, and treatment is an important subject in the medical and some relative areas, In recent years, with the development of the molecular biology in the cancer research,the study of molecular mechanism and withering had been further explored,but the occurrence mechanism of glioma is not clear.
GRIM-19(Gene associated with retinoid-IFN-induced mortality) which is induced by interferon/retinoic acid and can make cells deteriorate is a new gene chosen in the study of interferon-β; IFN-β and all-trans-retinoic acid, RA inducing cells to apoptosis by the way of delating opposite elements. GRIM-19is not belonged to any of the already known apoptosis gene.eg:Bcl-2,death recepor and caspase family. So far as concerned, GRIM-19participates in the process of cell proliferation and repoptosis,and the reduction of expression and site mutation may lead to the cell proliferation and vicious transformation. STAT3signal transduction pathway is a recently discovered cancer gene and it works as an important member in the gene family of transducing and transcribing the activator. The constant activating associates closely to the beginning and developing of tumor. It is discovered that the constitutive activation of STAT3plays a important role in the survival, proliferation, vasculogenesis, invasion and transferring, Immune escape.The suppression of STAT3signal Signal transduction pathway in and out of the body can restrain the cell proliferation and survival as well as inducing cells to apoptosis. GRIM-19is considered as a new negative regulator to express and activate STAT3. The study of GRIM-19in glioma is rare, and we can see no relative papers reporting GRIM-19and STAT3together. This research is to study its function in the beginning and developing of the glioma by the way of RT-PCR technical testing for the expression of GRIM-19mRNA and STAT3mRNA in the glioma tissues and non-neoplastic brain tissue so as to provide new idea in the clinic treatment for glioma.
Materials and Methods
45samples is got from the neurosurgery of the second Affiliated Hospital of Zhengzhou University. All the tumor samples are got from the parenchyma of the tumor, not including the central necrosis and Tumor border area,and they are through the diagnosis of the pathologist.All the samples are attacked for the first time,and they are not treated with radiotherapy and chemotherapy. Among them,there are28men and17women whose age is2-73years old,and the average age is37.23±16.35years old. The samples are stored in the liquid nitrogen after they are obtained and then transferred into the refrigerator of-80℃. They are strictly classified according to the the classification standard of the central nervous system tumors which is released by WHO in2007. Among them,there are5Ⅰ,18Ⅱ,12；,10Ⅳ. Ⅰ～Ⅱ belong to the lower malignancy group, the amount is23; Ⅲ-Ⅳ belong to the higher malignancy group,number22.Besides,13normal cerebral tissue samples of brain injury or cerebral hemorrhage patients are picked as normal control.After the RT-PCR test for the expression of GRIM-19mRNA、 STAT3gene mRNA in the45glioma tissues and the13tumor tissues. The result were analyzed with the statistics software of SPSS17.0. Probabiilty values a=0.05were considered statistically significant.
Results
1. The expression of GRIM-19mRNA in different grade glioma
GRIM-19mRNA presents low expression in glioma tissue specimens; high expression in the non-tumor brain tissue. The expression of GRIM-19mRNA in the non-tumor brain tissue,glioma tissue, low-grade malignant tumor tissues,highly malignant glioma group is respectively1.091、0.025、0.923、.076、0.986±040、0.856±0.040. The differences were significant between non-tumor brain tissue and glioma tissues, as well as between any two of the non-tumor brain tissue, low-grade malignant gliomas and high-grade gliomas.(P<0.05)
2.The expression in different grade glioma
STAT3mRNA presents high expression in glioma tissue specimens; low expression in the non-tumor brain tissue. The expression of STAT3mRNA in the non-tumor brain tissue,glioma tissue, low-grade malignant tumor tissues,highly malignant glioma group is respectively:0.671±0.020、0.818±0.049、0.786±0.030、0.843±0.041. The differences were significant between non-tumor brain tissue and glioma tissues, as well as between any two of the non-tumor brain tissue, low-grade malignant gliomas and high-grade gliomas.(P<0.05)
3.The relevancy between GRIM-19and STAT3
According to statistics,the expression of GRIM-19mRNA and STAT3mRNA is negative correlation,their expression is tend to opposite sides. The pearson relation is r=-0.618, P<0.05, and it makes sense in statistics.
Conclusions
1.The mRNA expression of GRIM-19gene in the glioma is obviously weakened which is compared to non-tumor brain tissue.As the pathological grade rises, the expression reduces gradually.
2.The mRNA expression of STAT3gene in the glioma is obviously strengthened which is compared to non-tumor brain tissue. As the pathological grade rises, the expression promotes gradually.
3.The expression of GRIM-19and STAT3presents negative correlation. GRIM-19and STAT3are expected to become the target spot in the diagnosis and treatment of glioma gene.
引文
[1]王忠诚.王忠诚神经外科学[M].南京：江苏科学技术出版社,2005：512
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