抑癌基因p16、Bcl11b及Ikaros与辐射诱发胸腺淋巴瘤的相关研究
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摘要
辐射致癌是电离辐射重要的生物效应之一,目前,随着核能在国民经济和军事领域中的广泛应用,辐射致癌的危险性受到更广泛关注。近年来,学者们对辐射致癌及其机制进行了深入研究,但辐射致癌的机理至今尚未彻底阐明。本研究利用辐射致癌的经典动物模型-辐射诱发小鼠胸腺淋巴瘤模型,探讨抑癌基因p16、Bcl11b及Ikaros基因在辐射致癌中的作用。本研究的创新点在于将分子生物学、遗传学及表观遗传学相结合探讨辐射致癌机制。
本研究采用基因芯片技术筛查基因表达谱改变;采用实时定量PCR及RT-PCR方法检测基因转录水平变化;采用Western Blot方法检测蛋白表达变化;采用PCR-RFLP方法检测基因SNPs;采用MSP及BSP方法检测基因DNA甲基化改变。结果证实,电离辐射可诱发胸腺淋巴瘤,其发生率BALB/c小鼠为58.51%,C57BL/6J小鼠为43.01%,两个品系小鼠辐射致癌敏感性存在差异。
基因芯片检测表明,BALB/c小鼠胸腺淋巴瘤细胞中基因表达谱发生改变,共有3063个差异表达基因,其中上调基因1591个,下调基因1472个,涉及KEGG数据库145个通路,BioCarta数据库76个通路及GenMAPP数据库218个通路。研究表明,胸腺淋巴瘤细胞中P16及Bcl11b蛋白表达均明显降低。时效研究表明,胸腺细胞中Bcl11b蛋白表达于照射后1~3个月明显降低。胸腺细胞中Ikaros mRNA水平于照射后3个月显著降低(P < 0.01)。遗传学研究表明,p16基因rs3695947位点、Ikaros基因rs28185870及rs28185923位点基因多态性的差别可能与电离辐射诱发胸腺淋巴瘤发生率的种系差异相关。表观遗传学研究证实,胸腺淋巴瘤细胞中p16基因启动子区CpG岛所检测的23个CpG位点中,第10及第11个CpG位点的DNA甲基化发生率均显著增高(P < 0.05,P < 0.01)。
以上结果提示,抑癌基因表达下调及DNA高度甲基化改变,可能在电离辐射诱发胸腺淋巴瘤中起重要作用。本研究所获结果将为进一步阐明辐射致癌机制提供新的生物学依据。
Ph.D. Student Liu Yongzhe Supervisor Prof. Ju Guizhi Radiation carcinogenesis is an important biological effect of ionizing radiation. Although many studies have been conducted, the mechanism of radiation carcinogenesis is still remaining unclear. In the present study we established a mouse thymic lymphoma model induced byγ-ray; employed gene chip to detect the difference of gene expression; used real-time PCR and RT-PCR to detect the level of gene transcription; adopted Western Blot to check the changes of protein expression; took PCR-RFLP to detect SNPs on target gene; and used MSP and BSP to detect the changes of DNA methylation. All these findings may explain the relationships among tumor suppressor genes p16, Bcl11b, Ikaros, and thymic lymphoma induced by ionizing radiation.
1 The establishment of mouse thymic lymphoma model induced by ionizing radiation
1.1 Mouse thymic lymphoma model induced by ionizing radiation We usedγ-ray to systemically irradiate mice BALB/c and C57BL/6J. The single dose was 1.75Gy per week continuing for 4 weeks. After 6 months irradiation, mice were executed. The thymus was taken out and undertaken gross specimen observation and pathology detection. At the meanwhile, we used the normal thymus of BALB/c and C57BL/6J as controls. According to the gross specimen observation results the mice with thymic lymphoma had an enlarged thymus with gray color, tough texture, adhesion significantly with the surrounding tissue, and some of mice were accompanied by pleural effusion by comparison with normal mice. Pathology results showed that the thymic organizational structure of the mice with thymic lymphoma was replaced by the diffuse proliferation of lymphoma cells. After calculation, the thymic lymphoma incidences induced by ionizing radiation were 58.51% (55/94) for BALB/c mice and 43.01% (40/93) for C57BL/6J mice. We also established 1-month model and 3-month model exposed to ionizing radiation for later use.
2 Changes of gene expression profile in thymic lymphoma cells induced by ionizing radiation
2.1 Differential expression genes in thymic lymphoma cells induced by ionizing radiation
We mixed BALB/c mouse thymic lymphoma and normal thymus respectively and sent to Shanghai Boxing Company for detection. The BeadChip Test of MouseWG-6 v2.0 genome-wide expression showed that a total of 3063 genes expressed differently between thymic lymphoma and normal thymus, including 1591 up-regulated genes, 1472 down-regulated genes.
2.2 Pathways of differential expression genes in thymic lymphoma cells induced by ionizing radiation
Differential expression genes in thymic lymphoma and normal thymus cells involved 145 pathways in the KEGG database, 76 pathways in the BioCarta database, and 218 pathways in the GenMAPP database according to the bio-molecular function annotation system on-line analysis of the BOAO MAS.
3 Gene transcription changes of p16, Bcl11b and Ikaros in thymic lymphoma cells induced by ionizing radiation
3.1 Changes of p16 mRNA in thymic lymphoma cells The real-time PCR was used to detect the changes of p16 mRNA in thymic lymphoma cells in BALB/c mice. There was no significant difference on p16 mRNA level between thymic lymphoma and normal thymus cells.
3.2 Changes of Bcl11b mRNA in thymic lymphoma cells The real-time PCR was used to detect the changes of Bcl11b mRNA in thymic lymphoma cells in BALB/c mice. There was no significant difference on Bcl11b mRNA level between thymic lymphoma and normal thymus cells.
3.3 Changes of Ikaros mRNA in thymic lymphoma cells
The real-time PCR was used to detect the changes of Ikaros mRNA in thymic lymphoma cells in BALB/c mice. There was no significant difference on Ikaros mRNA level between thymic lymphoma and normal thymus cells.
4 Protein expression changes of p16 and Bcl11b in thymic lymphoma cells induced by ionizing radiation
4.1 Changes of p16 protein in thymic lymphoma cell Western Blot was used to detect the changes of p16 protein expression in thymic lymphoma cells in BALB/c mice. We found that the p16 protein expression decreased in thymic lymphoma compared to normal thymus cell.
4.2 Changes of Bcl11b protein in thymic lymphoma cell Western Blot was used to detect the changes of Bcl11b protein expression in thymic lymphoma calls in BALB/c mice. We found that the Bcl11b protein expression decreased in thymic lymphoma compared to normal thymus cell.
5 Changes of gene transcription of p16, Bcl11b and Ikaros in mouse thymocytes before tumor formation
5.1 Changes of p16 mRNA in thymocytes
We used RT-PCR to detect the changes of p16 mRNA in thymus cells in BALB/c mice before tumor formation. The results indicated that there were no significant differences on p16 mRNA level in thymocytes among 1-month, 3-months irradiation and normal groups.
5.2 Changes of Bcl11b mRNA in thymocytes
We used RT-PCR to detect the changes of Bcl11b mRNA in thymus cells in BALB/c mice before tumor formation. The results indicated that there were no significant differences on Bcl11b mRNA level in thymocytes among 1-month, 3-months irradiation and normal groups.
5.3 Changes of Ikaros mRNA in thymocytes
We used RT-PCR to detect the changes of Ikaros mRNA in thymus cells in BALB/c mice before tumor formation. The results indicated that there were no significant differences on Ikaros mRNA level in thymocytes between 1-month irradiation and normal groups. The Ikaros mRNA level in 3-month irradiation group was significantly reduced compared to the normal thymocytes (P<0.01).
6 Changes of protein expression of p16, Bcl11b and Ikaros in mouse thymocytes before tumor formation
6.1 Changes of p16 protein expression in thymocytes Western Blot was employed to detect the changes of p16 protein expression in thymus cells in BALB/c mice before tumor formation. The results indicated that there were no significant differences on p16 protein expression in thymocytes among 1-month, 3-months irradiation and normal groups.
6.2 Changes of Bcl11b protein expression in thymocytes Western Blot was employed to detect the changes of Bcl11b protein expression in thymus cells in BALB/c mice before tumor formation. The results indicated that there were significant differences on Bcl11b protein expression in thymocytes among 1-month, 3-months irradiation and normal groups. The protein expression level of Bcl11b both in 1-month and 3-months irradiation groups were significantly reduced compared to the normal thymocytes.
7 The differences of germ-line in single nucleotide polymorphisms (SNPs)
7.1 The differences of p16 in SNPs between BALB/c and C57BL/6J mice The PCR-RFLP method was used to detect rs3695947 polymorphism on p16. The results showed that the genotype of rs3695947 is G/G in BALB/c mice and A/A in C57BL/6J mice.
7.2 The differences of Bcl11b in SNPs between BALB/c and C57BL/6J mice The PCR-RFLP method was used to detect rs33254541 polymorphism on Bcl11b. The results showed that the genotype of rs33254541 is T/T both in BALB/c and C57BL/6J mice.
7.3 The differences of Ikaros in SNPs between BALB/c and C57BL/6J mice The PCR-RFLP method was used to detect rs28185870 and rs28185923 polymorphism on Ikaros. The results showed that the genotypes of rs28185870 and rs28185923 are C/C, T/T in BALB/c mice respectively, and T/T, C/C in C57BL/6J mice respectively.
8 DNA methylation changes of p16, Bcl11b and Ikaros genes in thymic lymphoma cells
8.1 DNA methylation changes of CpG island in p16 promoter region in thymic lymphoma
MSP was used to detect the DNA methylation changes of CpG island in p16 promoter region in thymic lymphoma. The results showed that there were no DNA methylation changes of CpG island in p16 promoter region either in thymic lymphoma or normal thymic cells.
We used BSP methods to detect the DNA methylation changes of CpG island in p16 promoter region for thymic lymphoma. The results showed that the DNA methylations were significantly increased at the tenth and the eleventh among 23 CpG sites detected in p16 promoter region in thymic lymphoma (P<0.05, P<0.01respectively).
8.2 DNA methylation changes of CpG island in Bcl11b promoter region in thymic lymphoma BSP was used to detect the DNA methylation changes of CpG island in Bcl11b promoter region in thymic lymphoma. The results showed that there were no DNA methylation changes of CpG island in Bcl11b promoter region either in thymic lymphoma or normal thymic cells among 20 CpG sites.
8.3 DNA methylation changes of CpG island in Ikaros promoter region in thymic lymphoma
BSP was used to detect the DNA methylation changes of CpG island in Ikaros promoter region in thymic lymphoma. The results showed that there were one DNA methylation changes of CpG island in Ikaros promoter region both in thymic lymphoma and normal thymic cells among 50 CpG sites detected.
The present study will provide new biological evidence to elucidate the mechanisms for radiation carcinogenesis.
本研究采用基因芯片技术筛查基因表达谱改变;采用实时定量PCR及RT-PCR方法检测基因转录水平变化;采用Western Blot方法检测蛋白表达变化;采用PCR-RFLP方法检测基因SNPs;采用MSP及BSP方法检测基因DNA甲基化改变。结果证实,电离辐射可诱发胸腺淋巴瘤,其发生率BALB/c小鼠为58.51%,C57BL/6J小鼠为43.01%,两个品系小鼠辐射致癌敏感性存在差异。
基因芯片检测表明,BALB/c小鼠胸腺淋巴瘤细胞中基因表达谱发生改变,共有3063个差异表达基因,其中上调基因1591个,下调基因1472个,涉及KEGG数据库145个通路,BioCarta数据库76个通路及GenMAPP数据库218个通路。研究表明,胸腺淋巴瘤细胞中P16及Bcl11b蛋白表达均明显降低。时效研究表明,胸腺细胞中Bcl11b蛋白表达于照射后1~3个月明显降低。胸腺细胞中Ikaros mRNA水平于照射后3个月显著降低(P < 0.01)。遗传学研究表明,p16基因rs3695947位点、Ikaros基因rs28185870及rs28185923位点基因多态性的差别可能与电离辐射诱发胸腺淋巴瘤发生率的种系差异相关。表观遗传学研究证实,胸腺淋巴瘤细胞中p16基因启动子区CpG岛所检测的23个CpG位点中,第10及第11个CpG位点的DNA甲基化发生率均显著增高(P < 0.05,P < 0.01)。
以上结果提示,抑癌基因表达下调及DNA高度甲基化改变,可能在电离辐射诱发胸腺淋巴瘤中起重要作用。本研究所获结果将为进一步阐明辐射致癌机制提供新的生物学依据。
Ph.D. Student Liu Yongzhe Supervisor Prof. Ju Guizhi Radiation carcinogenesis is an important biological effect of ionizing radiation. Although many studies have been conducted, the mechanism of radiation carcinogenesis is still remaining unclear. In the present study we established a mouse thymic lymphoma model induced byγ-ray; employed gene chip to detect the difference of gene expression; used real-time PCR and RT-PCR to detect the level of gene transcription; adopted Western Blot to check the changes of protein expression; took PCR-RFLP to detect SNPs on target gene; and used MSP and BSP to detect the changes of DNA methylation. All these findings may explain the relationships among tumor suppressor genes p16, Bcl11b, Ikaros, and thymic lymphoma induced by ionizing radiation.
1 The establishment of mouse thymic lymphoma model induced by ionizing radiation
1.1 Mouse thymic lymphoma model induced by ionizing radiation We usedγ-ray to systemically irradiate mice BALB/c and C57BL/6J. The single dose was 1.75Gy per week continuing for 4 weeks. After 6 months irradiation, mice were executed. The thymus was taken out and undertaken gross specimen observation and pathology detection. At the meanwhile, we used the normal thymus of BALB/c and C57BL/6J as controls. According to the gross specimen observation results the mice with thymic lymphoma had an enlarged thymus with gray color, tough texture, adhesion significantly with the surrounding tissue, and some of mice were accompanied by pleural effusion by comparison with normal mice. Pathology results showed that the thymic organizational structure of the mice with thymic lymphoma was replaced by the diffuse proliferation of lymphoma cells. After calculation, the thymic lymphoma incidences induced by ionizing radiation were 58.51% (55/94) for BALB/c mice and 43.01% (40/93) for C57BL/6J mice. We also established 1-month model and 3-month model exposed to ionizing radiation for later use.
2 Changes of gene expression profile in thymic lymphoma cells induced by ionizing radiation
2.1 Differential expression genes in thymic lymphoma cells induced by ionizing radiation
We mixed BALB/c mouse thymic lymphoma and normal thymus respectively and sent to Shanghai Boxing Company for detection. The BeadChip Test of MouseWG-6 v2.0 genome-wide expression showed that a total of 3063 genes expressed differently between thymic lymphoma and normal thymus, including 1591 up-regulated genes, 1472 down-regulated genes.
2.2 Pathways of differential expression genes in thymic lymphoma cells induced by ionizing radiation
Differential expression genes in thymic lymphoma and normal thymus cells involved 145 pathways in the KEGG database, 76 pathways in the BioCarta database, and 218 pathways in the GenMAPP database according to the bio-molecular function annotation system on-line analysis of the BOAO MAS.
3 Gene transcription changes of p16, Bcl11b and Ikaros in thymic lymphoma cells induced by ionizing radiation
3.1 Changes of p16 mRNA in thymic lymphoma cells The real-time PCR was used to detect the changes of p16 mRNA in thymic lymphoma cells in BALB/c mice. There was no significant difference on p16 mRNA level between thymic lymphoma and normal thymus cells.
3.2 Changes of Bcl11b mRNA in thymic lymphoma cells The real-time PCR was used to detect the changes of Bcl11b mRNA in thymic lymphoma cells in BALB/c mice. There was no significant difference on Bcl11b mRNA level between thymic lymphoma and normal thymus cells.
3.3 Changes of Ikaros mRNA in thymic lymphoma cells
The real-time PCR was used to detect the changes of Ikaros mRNA in thymic lymphoma cells in BALB/c mice. There was no significant difference on Ikaros mRNA level between thymic lymphoma and normal thymus cells.
4 Protein expression changes of p16 and Bcl11b in thymic lymphoma cells induced by ionizing radiation
4.1 Changes of p16 protein in thymic lymphoma cell Western Blot was used to detect the changes of p16 protein expression in thymic lymphoma cells in BALB/c mice. We found that the p16 protein expression decreased in thymic lymphoma compared to normal thymus cell.
4.2 Changes of Bcl11b protein in thymic lymphoma cell Western Blot was used to detect the changes of Bcl11b protein expression in thymic lymphoma calls in BALB/c mice. We found that the Bcl11b protein expression decreased in thymic lymphoma compared to normal thymus cell.
5 Changes of gene transcription of p16, Bcl11b and Ikaros in mouse thymocytes before tumor formation
5.1 Changes of p16 mRNA in thymocytes
We used RT-PCR to detect the changes of p16 mRNA in thymus cells in BALB/c mice before tumor formation. The results indicated that there were no significant differences on p16 mRNA level in thymocytes among 1-month, 3-months irradiation and normal groups.
5.2 Changes of Bcl11b mRNA in thymocytes
We used RT-PCR to detect the changes of Bcl11b mRNA in thymus cells in BALB/c mice before tumor formation. The results indicated that there were no significant differences on Bcl11b mRNA level in thymocytes among 1-month, 3-months irradiation and normal groups.
5.3 Changes of Ikaros mRNA in thymocytes
We used RT-PCR to detect the changes of Ikaros mRNA in thymus cells in BALB/c mice before tumor formation. The results indicated that there were no significant differences on Ikaros mRNA level in thymocytes between 1-month irradiation and normal groups. The Ikaros mRNA level in 3-month irradiation group was significantly reduced compared to the normal thymocytes (P<0.01).
6 Changes of protein expression of p16, Bcl11b and Ikaros in mouse thymocytes before tumor formation
6.1 Changes of p16 protein expression in thymocytes Western Blot was employed to detect the changes of p16 protein expression in thymus cells in BALB/c mice before tumor formation. The results indicated that there were no significant differences on p16 protein expression in thymocytes among 1-month, 3-months irradiation and normal groups.
6.2 Changes of Bcl11b protein expression in thymocytes Western Blot was employed to detect the changes of Bcl11b protein expression in thymus cells in BALB/c mice before tumor formation. The results indicated that there were significant differences on Bcl11b protein expression in thymocytes among 1-month, 3-months irradiation and normal groups. The protein expression level of Bcl11b both in 1-month and 3-months irradiation groups were significantly reduced compared to the normal thymocytes.
7 The differences of germ-line in single nucleotide polymorphisms (SNPs)
7.1 The differences of p16 in SNPs between BALB/c and C57BL/6J mice The PCR-RFLP method was used to detect rs3695947 polymorphism on p16. The results showed that the genotype of rs3695947 is G/G in BALB/c mice and A/A in C57BL/6J mice.
7.2 The differences of Bcl11b in SNPs between BALB/c and C57BL/6J mice The PCR-RFLP method was used to detect rs33254541 polymorphism on Bcl11b. The results showed that the genotype of rs33254541 is T/T both in BALB/c and C57BL/6J mice.
7.3 The differences of Ikaros in SNPs between BALB/c and C57BL/6J mice The PCR-RFLP method was used to detect rs28185870 and rs28185923 polymorphism on Ikaros. The results showed that the genotypes of rs28185870 and rs28185923 are C/C, T/T in BALB/c mice respectively, and T/T, C/C in C57BL/6J mice respectively.
8 DNA methylation changes of p16, Bcl11b and Ikaros genes in thymic lymphoma cells
8.1 DNA methylation changes of CpG island in p16 promoter region in thymic lymphoma
MSP was used to detect the DNA methylation changes of CpG island in p16 promoter region in thymic lymphoma. The results showed that there were no DNA methylation changes of CpG island in p16 promoter region either in thymic lymphoma or normal thymic cells.
We used BSP methods to detect the DNA methylation changes of CpG island in p16 promoter region for thymic lymphoma. The results showed that the DNA methylations were significantly increased at the tenth and the eleventh among 23 CpG sites detected in p16 promoter region in thymic lymphoma (P<0.05, P<0.01respectively).
8.2 DNA methylation changes of CpG island in Bcl11b promoter region in thymic lymphoma BSP was used to detect the DNA methylation changes of CpG island in Bcl11b promoter region in thymic lymphoma. The results showed that there were no DNA methylation changes of CpG island in Bcl11b promoter region either in thymic lymphoma or normal thymic cells among 20 CpG sites.
8.3 DNA methylation changes of CpG island in Ikaros promoter region in thymic lymphoma
BSP was used to detect the DNA methylation changes of CpG island in Ikaros promoter region in thymic lymphoma. The results showed that there were one DNA methylation changes of CpG island in Ikaros promoter region both in thymic lymphoma and normal thymic cells among 50 CpG sites detected.
The present study will provide new biological evidence to elucidate the mechanisms for radiation carcinogenesis.
引文
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