癌基因c-Myc、Kras及Notch2与辐射诱发胸腺淋巴瘤的相关研究
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摘要
随着核电及核技术的应用越来越广泛,电离辐射对人类的潜在危害也不断增加,辐射致癌作为电离辐射对机体影响最大的远后效应,阐明辐射致癌机制,具有重要的理论与实际意义。
本研究通过60Coγ射线全身照射建立辐射诱发小鼠胸腺淋巴瘤动物模型,应用Illumina BeadChip分析胸腺淋巴瘤组织基因表达谱的变化,确定c-Myc、Kras和Notch2为目的基因,采用QRT-PCR、RT-PCR和Western blot技术对其在胸腺淋巴瘤发生过程中基因转录及蛋白表达水平进行检测,采用PCR-RFLP方法对目的基因的4个SNPs位点进行检测分型,采用BSP方法对目的基因启动子区CpG岛DNA甲基化进行研究。
实验结果表明,电离辐射可诱发小鼠胸腺淋巴瘤,在相同的照射条件下,C57BL/6J和BALB/c小鼠胸腺淋巴瘤的发生率不同,表现出一定的种系差异。胸腺淋巴瘤组织基因表达谱芯片共筛选差异表达基因3063个,其中上调基因1591个,下调基因1472个,基因的功能涉及信号转导、细胞周期调控、细胞凋亡、细胞增殖及转移等多个方面。胸腺淋巴瘤中c-Myc mRNA、Kras mRNA和Notch2 mRNA水平均显著增高(分别P<0.01;P<0.05;P<0.01),蛋白表达亦明显增高,并在肿瘤形成的过程中呈现一定的时效关系和辐射易感性差异。c-Myc基因rs51048361、Kras基因rs30221756和rs30161609及Notch2基因rs37563889位点,在C57BL/6J和BALB/c小鼠存在不同的基因型。辐射诱发胸腺淋巴瘤c-Myc、Kras和Notch2基因启动子区CpG位点DNA甲基化数量减少,呈去甲基化的趋势。
结果提示,c-Myc、Kras和Notch2基因可能与辐射致胸腺淋巴瘤的发生密切相关。在不同种系小鼠之间基因多态性的差异可能是导致胸腺淋巴瘤发生率不同的原因之一。电离辐射可能通过促使c-Myc、Kras及Notch2基因启动子区CpG岛DNA去甲基化而启动癌基因的活化,导致其过度表达,在辐射致胸腺淋巴瘤中发挥重要作用。本研究将为辐射致癌机制的阐明提供新的实验依据。
Ionizing radiation is a definite factor in carcinogenesis. With the usage of nuclear energy widely in the economic and military fields, the potential hazards of ionizing radiation are increasing on the human. Radiation carcinogenesis is the greatest impact on the body from after-effects of ionizing radiation, whose molecular mechanism is the focus of oncology, radiobiology, radiation protection and preventive medicine. The traditional view is that radiation leads to gene mutation, deletion, amplification, rearrangement by inducing DNA damage, thus chromosome aberrations and malignant transformation. However, radiation-induced DNA chromosome damage is not the only cause to all of these changes. Radiation-induced changes of DNA methylation patterns might be another mechanism of radiation carcinogenesis.
1. Objective
In this study, the radiation-induced thymic lymphoma models of mice were established by whole body irradiation. To analyze the changes of gene expressions in thymic lymphoma by Illumina BeadChip, then to determine the target genes and detect the expression level during the process of forming thymus lymphoma. Single nucleotide polymorphisms (SNPs) genotype was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. DNA methylation of CpG island in promoter region was detected by bisulfate-sequencing PCR (BSP). In order to investigate the relevance between the target genes and radiation carcinogenesis from genetics and epigenetics, it will provide experimental basis for clarify the molecular mechanism of radiation carcinogenesis.
2. Methods
Radiation-induced thymic lymphoma models were made by whole body irradiation with 60Coγ-ray, fractionated exposure to BALB/c and C57BL6/J mice(1.75 Gy, one time a week, four consecutive times, total dose:7Gy). The following techniques were used: gene chip technology for thymic lymphoma gene expression map; QRT-PCR and RT-PCR for gene transcription level; Western blot for protein expression; PCR-RFLP for SNPs; BSP for DNA methylation of CpG island in promoter region.
3. Results
3.1 Making radiation-induced thymic lymphoma models of mice
The animal models of thymic lymphoma induced by ionizing radiation were established successfully. The rates of thymic lymphoma were 43.01% (40/93) in C57BL/6J mice and 58.51% (55/94) in BALB/c mice. The incidences of thymic lymphoma were different in C57BL/6J and BALB/c mice under the same irradiation conditions, which showed the germline difference.
3.2 Analysis on gene expression map of radiation-induced thymic lymphoma
Gene expression differences were analysed by Cubic Spline normalization method. The results showed that 31492 gene expressions in thymic lymphoma and 45281 gene expressions in control BALB/c mice were detected respectively. There were 3063 varied gene expressions between two groups (screening criteria: it must be effective gene in the experimental group and control group, at the same time, diffscore value is less than -20 or greater than +20 in experimental group), including 1591 up-regulated genes and 1472 down-regulated genes. The functions of differentially expressed genes involved in signal transduction, cell cycle regulation, apoptosis and cell proliferation, etc.
3.3 Affection on c-Myc, Kras and Notch2 gene expression by ionizing radiation
QRT-PCR and RT-PCR test results showed that c-Myc mRNA, Kras mRNA and Notch2 mRNA were significantly increased in thymic lymphoma cells compared with control group (P<0.01, P<0.05, P<0.01 respectively). Protein expressions also increased markedly in thymic lymphoma cells by western blot, in which the tendency was basically accordance with the transcription level.
After 1 month exposure of BALB/c mice to ionizing radiation, the changes of the expression of c-Myc mRNA, Kras mRNA and Notch2 mRNA level by RT-PCR were not significantly in thymic lymphoma cells compared with control (P>0.05 respectively ). The protein levels were also no obvious changes by Western blot in thymic lymphoma cells. After 3 month exposure of BALB/c mice to ionizing radiation, the expressions of c-Myc mRNA and Kras mRNA were increased significantly in thymic lymphoma cells compared with control group (P <0.01, P <0.05 respectively), while the expression of Notch2 mRNA was not significant (P> 0.05). The protein expressions of c-Myc and Kras were higher in irradiation group than in control group by Western blot, while the Notch2 protein expression did not change significantly.
3.4 Changes of single nucleotide polymorphisms in thymic lymphoma
The genotypes of 4 SNPs containing restriction endonuclease sites, including c-Myc gene rs51048361, Kras gene rs30221756 and rs30161609 , Notch2 gene rs37563889, were detected by PCR-RFLP method in radiation-induced thymic lymphoma cells of BALB/c and C57BL/6J mice. The results showed that the genotype of rs51048361 was C/C in BALB/c mice and T/T in C57BL/6J; the genotype of rs30221756 was A/A in BALB/c mice and G/G in C57BL/6J mice; the genotype of rs30161609 was T/T in BALB/c mice and C/C in C57BL/6J mice; the genotype of rs37563889 was C/C in BALB / c mice and G/G in C57BL/6J mice.
3.5 Changes on DNA methylation of CpG island in c-Myc, Kras and Notch2 gene promoter regions in thymic lymphoma
DNA methylation of CpG island was detected by BSP. The results showed that 3 and 16 CpG sites of c-Myc gene were methylated in control group. However there were not methylation sites were found in thymic lymphoma group.
The results showed that in control group, 3, 9, 22, 23, 24, 25, 26, 27, 29, 30, 31, 38, 40, 41, 48 and 55 CpG sites of Kras gene were methylated and 4, 7, 9, 23, 24, 31, 38, 40, 51, 53, 54 and 59 CpG sites were methylated in thymus lymphoma group. The decrease of the number of methylation sites in thymic lymphoma was not significant compared with control group(P>0.05).
The results showed that in control group, 13, 17, 18, 21, 25, 26 and 28 CpG sites of Notch2 gene were methylated and 8, 13, 29, 37 and 40 CpG sites were methylated in thymus lymphoma group. The decrease of the number of methylation sites in thymic lymphoma was not significant compared with control group(P>0.05).
4. Conclusion
Animal experiments showed that ionizing radiation could induce thymic lymphoma of mice. Under the same irradiation conditions, the incidences of thymic lymphoma in C57BL/6J and BALB/c mice were different, which showed the differences in the germ-line. Genetic study confirmed that c-Myc gene rs51048361, Kras gene rs30221756, rs30161609 and Notch2 gene rs37563889 locus showed different genotypes in C57BL/6J and BALB/c mice. The changes of gene polymorphisms might be related to different incidences of radiation-induced thymic lymphoma in various germ-line.
Gene chips results showed that the number of differentially expressed genes in thymus lymphoma mice was 3063, in which up-regulated genes were 1591 and down-regulated genes were 1472. The function of differentially expressed genes involved in signal transduction, cell cycle regulation, apoptosis and cell proliferation, etc. It showed that the occurrence of radiation-induced lymphoma was a complex process involving multiple genes.
Gene transcription and protein expression of c-Myc, Kras and Notch2 were significantly increased in thymic lymphoma. It suggests that these genes might be relevant to the occurrence of radiation-induced thymic lymphoma. Time-effect experiments confirmed that the changes of c-Myc and Kras gene transcription and protein expression in thymus cells were no significant at 1 month after irradiation, and 3 month later, the expressions were significantly increased, which showed a time-effect relationship. The transcription and protein expression of Notch2 gene did not change significantly, which showed that the radiation susceptibility was poor relatively.
DNA methylation results showed that ionizing radiation might promote DNA demethylation of c-Myc, Kras and Notch2 gene CpG islands and activate the oncogenes, then lead genes to over-expression, which might be important mechanisms for the occurrence of thymic lymphoma induced by ionizing radiation. These results will provide important experimental evidence for the clarification of radiation carcinogenesis.
本研究通过60Coγ射线全身照射建立辐射诱发小鼠胸腺淋巴瘤动物模型,应用Illumina BeadChip分析胸腺淋巴瘤组织基因表达谱的变化,确定c-Myc、Kras和Notch2为目的基因,采用QRT-PCR、RT-PCR和Western blot技术对其在胸腺淋巴瘤发生过程中基因转录及蛋白表达水平进行检测,采用PCR-RFLP方法对目的基因的4个SNPs位点进行检测分型,采用BSP方法对目的基因启动子区CpG岛DNA甲基化进行研究。
实验结果表明,电离辐射可诱发小鼠胸腺淋巴瘤,在相同的照射条件下,C57BL/6J和BALB/c小鼠胸腺淋巴瘤的发生率不同,表现出一定的种系差异。胸腺淋巴瘤组织基因表达谱芯片共筛选差异表达基因3063个,其中上调基因1591个,下调基因1472个,基因的功能涉及信号转导、细胞周期调控、细胞凋亡、细胞增殖及转移等多个方面。胸腺淋巴瘤中c-Myc mRNA、Kras mRNA和Notch2 mRNA水平均显著增高(分别P<0.01;P<0.05;P<0.01),蛋白表达亦明显增高,并在肿瘤形成的过程中呈现一定的时效关系和辐射易感性差异。c-Myc基因rs51048361、Kras基因rs30221756和rs30161609及Notch2基因rs37563889位点,在C57BL/6J和BALB/c小鼠存在不同的基因型。辐射诱发胸腺淋巴瘤c-Myc、Kras和Notch2基因启动子区CpG位点DNA甲基化数量减少,呈去甲基化的趋势。
结果提示,c-Myc、Kras和Notch2基因可能与辐射致胸腺淋巴瘤的发生密切相关。在不同种系小鼠之间基因多态性的差异可能是导致胸腺淋巴瘤发生率不同的原因之一。电离辐射可能通过促使c-Myc、Kras及Notch2基因启动子区CpG岛DNA去甲基化而启动癌基因的活化,导致其过度表达,在辐射致胸腺淋巴瘤中发挥重要作用。本研究将为辐射致癌机制的阐明提供新的实验依据。
Ionizing radiation is a definite factor in carcinogenesis. With the usage of nuclear energy widely in the economic and military fields, the potential hazards of ionizing radiation are increasing on the human. Radiation carcinogenesis is the greatest impact on the body from after-effects of ionizing radiation, whose molecular mechanism is the focus of oncology, radiobiology, radiation protection and preventive medicine. The traditional view is that radiation leads to gene mutation, deletion, amplification, rearrangement by inducing DNA damage, thus chromosome aberrations and malignant transformation. However, radiation-induced DNA chromosome damage is not the only cause to all of these changes. Radiation-induced changes of DNA methylation patterns might be another mechanism of radiation carcinogenesis.
1. Objective
In this study, the radiation-induced thymic lymphoma models of mice were established by whole body irradiation. To analyze the changes of gene expressions in thymic lymphoma by Illumina BeadChip, then to determine the target genes and detect the expression level during the process of forming thymus lymphoma. Single nucleotide polymorphisms (SNPs) genotype was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. DNA methylation of CpG island in promoter region was detected by bisulfate-sequencing PCR (BSP). In order to investigate the relevance between the target genes and radiation carcinogenesis from genetics and epigenetics, it will provide experimental basis for clarify the molecular mechanism of radiation carcinogenesis.
2. Methods
Radiation-induced thymic lymphoma models were made by whole body irradiation with 60Coγ-ray, fractionated exposure to BALB/c and C57BL6/J mice(1.75 Gy, one time a week, four consecutive times, total dose:7Gy). The following techniques were used: gene chip technology for thymic lymphoma gene expression map; QRT-PCR and RT-PCR for gene transcription level; Western blot for protein expression; PCR-RFLP for SNPs; BSP for DNA methylation of CpG island in promoter region.
3. Results
3.1 Making radiation-induced thymic lymphoma models of mice
The animal models of thymic lymphoma induced by ionizing radiation were established successfully. The rates of thymic lymphoma were 43.01% (40/93) in C57BL/6J mice and 58.51% (55/94) in BALB/c mice. The incidences of thymic lymphoma were different in C57BL/6J and BALB/c mice under the same irradiation conditions, which showed the germline difference.
3.2 Analysis on gene expression map of radiation-induced thymic lymphoma
Gene expression differences were analysed by Cubic Spline normalization method. The results showed that 31492 gene expressions in thymic lymphoma and 45281 gene expressions in control BALB/c mice were detected respectively. There were 3063 varied gene expressions between two groups (screening criteria: it must be effective gene in the experimental group and control group, at the same time, diffscore value is less than -20 or greater than +20 in experimental group), including 1591 up-regulated genes and 1472 down-regulated genes. The functions of differentially expressed genes involved in signal transduction, cell cycle regulation, apoptosis and cell proliferation, etc.
3.3 Affection on c-Myc, Kras and Notch2 gene expression by ionizing radiation
QRT-PCR and RT-PCR test results showed that c-Myc mRNA, Kras mRNA and Notch2 mRNA were significantly increased in thymic lymphoma cells compared with control group (P<0.01, P<0.05, P<0.01 respectively). Protein expressions also increased markedly in thymic lymphoma cells by western blot, in which the tendency was basically accordance with the transcription level.
After 1 month exposure of BALB/c mice to ionizing radiation, the changes of the expression of c-Myc mRNA, Kras mRNA and Notch2 mRNA level by RT-PCR were not significantly in thymic lymphoma cells compared with control (P>0.05 respectively ). The protein levels were also no obvious changes by Western blot in thymic lymphoma cells. After 3 month exposure of BALB/c mice to ionizing radiation, the expressions of c-Myc mRNA and Kras mRNA were increased significantly in thymic lymphoma cells compared with control group (P <0.01, P <0.05 respectively), while the expression of Notch2 mRNA was not significant (P> 0.05). The protein expressions of c-Myc and Kras were higher in irradiation group than in control group by Western blot, while the Notch2 protein expression did not change significantly.
3.4 Changes of single nucleotide polymorphisms in thymic lymphoma
The genotypes of 4 SNPs containing restriction endonuclease sites, including c-Myc gene rs51048361, Kras gene rs30221756 and rs30161609 , Notch2 gene rs37563889, were detected by PCR-RFLP method in radiation-induced thymic lymphoma cells of BALB/c and C57BL/6J mice. The results showed that the genotype of rs51048361 was C/C in BALB/c mice and T/T in C57BL/6J; the genotype of rs30221756 was A/A in BALB/c mice and G/G in C57BL/6J mice; the genotype of rs30161609 was T/T in BALB/c mice and C/C in C57BL/6J mice; the genotype of rs37563889 was C/C in BALB / c mice and G/G in C57BL/6J mice.
3.5 Changes on DNA methylation of CpG island in c-Myc, Kras and Notch2 gene promoter regions in thymic lymphoma
DNA methylation of CpG island was detected by BSP. The results showed that 3 and 16 CpG sites of c-Myc gene were methylated in control group. However there were not methylation sites were found in thymic lymphoma group.
The results showed that in control group, 3, 9, 22, 23, 24, 25, 26, 27, 29, 30, 31, 38, 40, 41, 48 and 55 CpG sites of Kras gene were methylated and 4, 7, 9, 23, 24, 31, 38, 40, 51, 53, 54 and 59 CpG sites were methylated in thymus lymphoma group. The decrease of the number of methylation sites in thymic lymphoma was not significant compared with control group(P>0.05).
The results showed that in control group, 13, 17, 18, 21, 25, 26 and 28 CpG sites of Notch2 gene were methylated and 8, 13, 29, 37 and 40 CpG sites were methylated in thymus lymphoma group. The decrease of the number of methylation sites in thymic lymphoma was not significant compared with control group(P>0.05).
4. Conclusion
Animal experiments showed that ionizing radiation could induce thymic lymphoma of mice. Under the same irradiation conditions, the incidences of thymic lymphoma in C57BL/6J and BALB/c mice were different, which showed the differences in the germ-line. Genetic study confirmed that c-Myc gene rs51048361, Kras gene rs30221756, rs30161609 and Notch2 gene rs37563889 locus showed different genotypes in C57BL/6J and BALB/c mice. The changes of gene polymorphisms might be related to different incidences of radiation-induced thymic lymphoma in various germ-line.
Gene chips results showed that the number of differentially expressed genes in thymus lymphoma mice was 3063, in which up-regulated genes were 1591 and down-regulated genes were 1472. The function of differentially expressed genes involved in signal transduction, cell cycle regulation, apoptosis and cell proliferation, etc. It showed that the occurrence of radiation-induced lymphoma was a complex process involving multiple genes.
Gene transcription and protein expression of c-Myc, Kras and Notch2 were significantly increased in thymic lymphoma. It suggests that these genes might be relevant to the occurrence of radiation-induced thymic lymphoma. Time-effect experiments confirmed that the changes of c-Myc and Kras gene transcription and protein expression in thymus cells were no significant at 1 month after irradiation, and 3 month later, the expressions were significantly increased, which showed a time-effect relationship. The transcription and protein expression of Notch2 gene did not change significantly, which showed that the radiation susceptibility was poor relatively.
DNA methylation results showed that ionizing radiation might promote DNA demethylation of c-Myc, Kras and Notch2 gene CpG islands and activate the oncogenes, then lead genes to over-expression, which might be important mechanisms for the occurrence of thymic lymphoma induced by ionizing radiation. These results will provide important experimental evidence for the clarification of radiation carcinogenesis.
引文
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