放射线对小鼠组织线粒体基因和鼻咽癌细胞生物学行为影响的初步研究
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摘要
第一部分：放射线与缬沙坦联合对鼻咽癌细胞生物学效应的影响
目的：研究血管紧张素Ⅱ(AngⅡ)及其受体(AT1R)阻滞剂缬沙坦(valsartan)和gamma射线联合对人鼻咽癌细胞系(CNE-2)的VEGF基因表达,细胞增生与侵袭,放射敏感性的影响。
方法：用RT-PCR和ELISA分别检测在干预前后CNE-2细胞血管内皮生长因子(VEGF)的基因和蛋白水平表达变化。用MTT检测AngⅡ对CNE-2细胞增殖的作用。用体外侵袭实验测定AngⅡ及缬沙坦对鼻咽癌细胞CNE-2侵袭力的影响。用成克隆分析法观察缬沙坦与放射联合对CNE-2细胞体外存活效应的影响,用流式细胞术和体外侵袭实验(小室法)检测对细胞凋亡和侵袭能力的影响。
结果：AngⅡ可以诱导CNE-2表达VEGF上调,对照组与10-9,10-8,10-7mol/L AngⅡ组VEGF分泌分别为246和350,521.5,595.5 pg/105 cell。AngⅡ还能诱导CNE-2增殖和侵袭,经10-9,10-8,10-7mol/L AngⅡ处理后,侵袭细胞数分别为103,111,124,较对照组均有所增高。缬沙坦可以抑制AngⅡ的这些作用(p<0.05)。在与gamma射线联合的实验中,CNE-2细胞经10-9、10-8、10-7mol/L缬沙坦与放射联合作用后,放射增敏比(SER)分别为1.10、1.20、1.36。细胞侵袭能力在6Gy gammma射线和缬沙坦作用下,抑制率分别为8.11%、16.77%、16.49%。经10-7mol/L缬沙坦和8Gy gamma放射线处理并孵育24h后,CNE-2细胞凋亡率为6.17%±0.22%,与单纯放射组2.44%±0.72%相比有所提高(P<0.05)。
结论：AngⅡ可以诱导鼻咽癌细胞CNE-2增殖和侵袭,AT1R阻滞剂缬沙坦能抑制这种作用,其机制可能涉及对VEGF的表达调控。不仅如此,AT1R阻滞剂还能在体外对细胞有放射增敏作用,与放射联合能抑制细胞侵袭能力和在一定程度诱导细胞凋亡,这些可为缬沙坦体内实验的放射增敏效应提供基础。
第二部分：放射线诱导下线粒体基因在小鼠组织中的变化
目的：研究小鼠在放射线下线粒体基因拷贝数的改变。
方法：所有石蜡组织来源于全身接受gamma和中子线照射的小鼠,相似的总剂量(550cGy)和三种不同水平的剂量率以及照射分次为我们选择的实验分组。来源于5Gy gamma射线照射后的新鲜小鼠组织在24小时后被取出同样应用于该实验。实时定量PCR中绝对定量的方法被选择检测线粒体编码的线粒体基因COX1, ND1, MTATP6和ATPCYB,同时与之相对应的细胞核编码的线粒体基因COX6B, NDUFV1, ATP5A1和CYB5B作为参照基因也会被检测。它们的配对比值最终参与统计计算。
结果：石蜡组织中,小鼠不同组织对放射线有不同的反应。中子射线在相同总剂量条件下较gamma射线对组织线粒体基因组有更大的损伤作用,并且它会诱导下调线粒体基因的拷贝数,这与gamma射线的上调作用是完全相反的。在单个组织分析中,脾脏组织,心脏组织和肾脏单次照射和较高剂量率的gamma射线实验组才能使线粒体基因的拷贝显著性升高。类似的结果在新鲜小鼠实验中也同样被观察到。除了放射线,在三种被检测的组织中,多种疾病和小鼠死亡年龄都能显著性改变线粒体基因拷贝数。
结论：小鼠线粒体基因拷贝数会因放射线的作用,所患多种疾病和死亡年龄的改变而发生改变。仅急性gamma放射线才会产生显著影响,所涉及的机制可能与线粒体基因组的复制和修复机制有关。
Part one:Valsartan inhibiting NPC cell line CNE-2 proliferation and invasion and promoting its sensitivity to radiation
Objectives:To investigate the effects of Angiotensin II and valsartan, an AngiotensinⅡtype 1 receptor (AT1R) blocker, combined with y-radiation on VEGF expression, radiosensitivity, invasive potential, and proliferation activity of nasopharyngeal carcinoma (CNE-2) in vitro.
Methods:RT-PCR and ELISA assayed VEGF expression and secretion in CNE-2 in vitro. Radiosensitization of valsartan on CNE-2 cell in vitro was investigated by a colony forming assay. Effect of AT1R blocker combined with radiation on invasive potential of CNE-2 cell was evaluated using 24 well Matrigel invasion chambers (Transwell). Apoptosis-inducing effect of valsartan combined with irradiation on apoptosis of CNE-2 was identified by flowcytometry (FCM)
Results:AT1R was expressed in nasopharyngeal carcinoma cell lines CNE-1 and CNE-2. The expression and secretion of VEGF in CNE-2 could be induced either by Angiotensin II or y-radiation. Furthermore, the suppression of AT1R activation reduced cellular proliferation, invasive potential and resistance to y-radiation in nasopharyngeal carcinoma cells.
Conclusion:AT1R plays a significant role not only in proliferation and invasion, but also in radiation resistance in nasopharyngeal carcinoma cells, the mechanism of which may be involved in the regulation of VEGF expression and secretion.
Part two:Radiation-Induced Mitochondrial Genes Changes in Mice
Objectives:To investigate the effects of radiation on the mice mitochondrial genome in vivo.
Methods:Paraffin tissues were selected from mice that whole body exposed to gamma or neutron radiation, similar total dose (550 cGy) and 3 levels of dose rates and fractions were set up. Fresh mice tissues were got from normal mice at 24 hours after 5Gy gamma radiation. Absolute quantification of Realtime-PCR was used to assay the mitochondrial-encoded mitochondrial genes COX1, ND1, MTATP6 and ATPCYB while corresponding nucleus-encoded mitochondrial genes COX6B, NDUFV1, ATP5A1 and CYB5B also were tested. The ratios of each pairgenes were calculated finally.
Results:Different tissues have different response to radiation in paraffin tissues from mice. Neutron radiation can bring worse effect than gamma radiation and mtDNA gene copy number decreased other than increased that showed in gamma radiation group. Just one fraction gamma radiation can significantly increase the mtDNA gene copy number in spleen, heart and kidney. Similar results were observed in fresh mice experiment. Besides radiation, kinds of disease and age of death of mice can also influence the mtDNA gene copy number in all tested tissues.
Conclusion:mitochondrial DNA gene copy number was varied under radiation, different age of death and disease with tissue specificity. Just acute gamma radiation showed significant effects which may be involved in the mtDNA genome replication and repair mechanism.
目的：研究血管紧张素Ⅱ(AngⅡ)及其受体(AT1R)阻滞剂缬沙坦(valsartan)和gamma射线联合对人鼻咽癌细胞系(CNE-2)的VEGF基因表达,细胞增生与侵袭,放射敏感性的影响。
方法：用RT-PCR和ELISA分别检测在干预前后CNE-2细胞血管内皮生长因子(VEGF)的基因和蛋白水平表达变化。用MTT检测AngⅡ对CNE-2细胞增殖的作用。用体外侵袭实验测定AngⅡ及缬沙坦对鼻咽癌细胞CNE-2侵袭力的影响。用成克隆分析法观察缬沙坦与放射联合对CNE-2细胞体外存活效应的影响,用流式细胞术和体外侵袭实验(小室法)检测对细胞凋亡和侵袭能力的影响。
结果：AngⅡ可以诱导CNE-2表达VEGF上调,对照组与10-9,10-8,10-7mol/L AngⅡ组VEGF分泌分别为246和350,521.5,595.5 pg/105 cell。AngⅡ还能诱导CNE-2增殖和侵袭,经10-9,10-8,10-7mol/L AngⅡ处理后,侵袭细胞数分别为103,111,124,较对照组均有所增高。缬沙坦可以抑制AngⅡ的这些作用(p<0.05)。在与gamma射线联合的实验中,CNE-2细胞经10-9、10-8、10-7mol/L缬沙坦与放射联合作用后,放射增敏比(SER)分别为1.10、1.20、1.36。细胞侵袭能力在6Gy gammma射线和缬沙坦作用下,抑制率分别为8.11%、16.77%、16.49%。经10-7mol/L缬沙坦和8Gy gamma放射线处理并孵育24h后,CNE-2细胞凋亡率为6.17%±0.22%,与单纯放射组2.44%±0.72%相比有所提高(P<0.05)。
结论：AngⅡ可以诱导鼻咽癌细胞CNE-2增殖和侵袭,AT1R阻滞剂缬沙坦能抑制这种作用,其机制可能涉及对VEGF的表达调控。不仅如此,AT1R阻滞剂还能在体外对细胞有放射增敏作用,与放射联合能抑制细胞侵袭能力和在一定程度诱导细胞凋亡,这些可为缬沙坦体内实验的放射增敏效应提供基础。
第二部分：放射线诱导下线粒体基因在小鼠组织中的变化
目的：研究小鼠在放射线下线粒体基因拷贝数的改变。
方法：所有石蜡组织来源于全身接受gamma和中子线照射的小鼠,相似的总剂量(550cGy)和三种不同水平的剂量率以及照射分次为我们选择的实验分组。来源于5Gy gamma射线照射后的新鲜小鼠组织在24小时后被取出同样应用于该实验。实时定量PCR中绝对定量的方法被选择检测线粒体编码的线粒体基因COX1, ND1, MTATP6和ATPCYB,同时与之相对应的细胞核编码的线粒体基因COX6B, NDUFV1, ATP5A1和CYB5B作为参照基因也会被检测。它们的配对比值最终参与统计计算。
结果：石蜡组织中,小鼠不同组织对放射线有不同的反应。中子射线在相同总剂量条件下较gamma射线对组织线粒体基因组有更大的损伤作用,并且它会诱导下调线粒体基因的拷贝数,这与gamma射线的上调作用是完全相反的。在单个组织分析中,脾脏组织,心脏组织和肾脏单次照射和较高剂量率的gamma射线实验组才能使线粒体基因的拷贝显著性升高。类似的结果在新鲜小鼠实验中也同样被观察到。除了放射线,在三种被检测的组织中,多种疾病和小鼠死亡年龄都能显著性改变线粒体基因拷贝数。
结论：小鼠线粒体基因拷贝数会因放射线的作用,所患多种疾病和死亡年龄的改变而发生改变。仅急性gamma放射线才会产生显著影响,所涉及的机制可能与线粒体基因组的复制和修复机制有关。
Part one:Valsartan inhibiting NPC cell line CNE-2 proliferation and invasion and promoting its sensitivity to radiation
Objectives:To investigate the effects of Angiotensin II and valsartan, an AngiotensinⅡtype 1 receptor (AT1R) blocker, combined with y-radiation on VEGF expression, radiosensitivity, invasive potential, and proliferation activity of nasopharyngeal carcinoma (CNE-2) in vitro.
Methods:RT-PCR and ELISA assayed VEGF expression and secretion in CNE-2 in vitro. Radiosensitization of valsartan on CNE-2 cell in vitro was investigated by a colony forming assay. Effect of AT1R blocker combined with radiation on invasive potential of CNE-2 cell was evaluated using 24 well Matrigel invasion chambers (Transwell). Apoptosis-inducing effect of valsartan combined with irradiation on apoptosis of CNE-2 was identified by flowcytometry (FCM)
Results:AT1R was expressed in nasopharyngeal carcinoma cell lines CNE-1 and CNE-2. The expression and secretion of VEGF in CNE-2 could be induced either by Angiotensin II or y-radiation. Furthermore, the suppression of AT1R activation reduced cellular proliferation, invasive potential and resistance to y-radiation in nasopharyngeal carcinoma cells.
Conclusion:AT1R plays a significant role not only in proliferation and invasion, but also in radiation resistance in nasopharyngeal carcinoma cells, the mechanism of which may be involved in the regulation of VEGF expression and secretion.
Part two:Radiation-Induced Mitochondrial Genes Changes in Mice
Objectives:To investigate the effects of radiation on the mice mitochondrial genome in vivo.
Methods:Paraffin tissues were selected from mice that whole body exposed to gamma or neutron radiation, similar total dose (550 cGy) and 3 levels of dose rates and fractions were set up. Fresh mice tissues were got from normal mice at 24 hours after 5Gy gamma radiation. Absolute quantification of Realtime-PCR was used to assay the mitochondrial-encoded mitochondrial genes COX1, ND1, MTATP6 and ATPCYB while corresponding nucleus-encoded mitochondrial genes COX6B, NDUFV1, ATP5A1 and CYB5B also were tested. The ratios of each pairgenes were calculated finally.
Results:Different tissues have different response to radiation in paraffin tissues from mice. Neutron radiation can bring worse effect than gamma radiation and mtDNA gene copy number decreased other than increased that showed in gamma radiation group. Just one fraction gamma radiation can significantly increase the mtDNA gene copy number in spleen, heart and kidney. Similar results were observed in fresh mice experiment. Besides radiation, kinds of disease and age of death of mice can also influence the mtDNA gene copy number in all tested tissues.
Conclusion:mitochondrial DNA gene copy number was varied under radiation, different age of death and disease with tissue specificity. Just acute gamma radiation showed significant effects which may be involved in the mtDNA genome replication and repair mechanism.
引文
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