鼻咽癌氧化性DNA损伤及其作用机制的研究
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摘要
研究目的：
运用双色免疫荧光组织化学方法以及酶联免疫吸附试验分别检测鼻咽癌鼻咽组织及血清中氧化性DNA损伤的情况,并且运用荧光原位杂交技术检测鼻咽癌组织中EB病毒感染的情况,初步探索鼻咽癌的发生和发展是否与氧化性DNA损伤有关及其损伤的可能原因和途径,以期寻找出能够辅助鼻咽癌诊断的生物标志物。
方法：
(1)选择57例鼻咽癌患者和39例慢性鼻咽炎患者鼻咽部组织,采用双色免疫荧光组织化学方法分别检测8-硝基鸟嘌呤(8-nitroguanine, 8-NitroG),8-羟基脱氧鸟苷(8-hydroxy-2'-deoxyguanosine,8-OHdG)和诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)的免疫反应。秩和检验统计学方法分析鼻咽癌和慢性鼻咽炎鼻咽组织之间8-NitroG、8-OHdG和iNOS免疫反应强度的差异。
(2)从57例鼻咽癌中随机选择36例鼻咽癌患者和36例健康人血清标本,采用酶联免疫吸附试验方法(enzyme-linked immunosorbent assay, ELISA)检测血清中8-羟基脱氧鸟苷(8-OHdG)的表达水平。采用成组t检验进行数据的统计学分析。
(3)选择57例鼻咽癌患者和39例慢性鼻咽炎患者鼻咽部组织,采用双色免疫荧光组织化学方法分别检测磷酸化的信号转导及转录激活因子(phosphorylated signal transducers and activators of transcription, p-Stat3),表皮生长因子受体(epidermal growth factor receptor, EGFR)的免疫反应。秩和检验统计学方法分析鼻咽癌和慢性咽炎鼻咽组织之间p-Stat3.EGFR免疫反应强度的差异。
(4)选择57例鼻咽癌患者和39例慢性鼻咽炎患者鼻咽部组织,采用双色免疫荧光组织化学方法分别检测鼻咽癌组织中巨噬细胞的表面抗原CD68及其表达产物IL-6的免疫反应。秩和检验统计学方法分析鼻咽癌和慢性鼻咽炎鼻咽组织之间CD68、IL-6免疫反应强度的差异。
(5)选择57例鼻咽癌患者和39例慢性鼻咽炎患者鼻咽部组织,采用荧光原位杂交法(fluorescent in situ hybridization, FISH)检测鼻咽癌组织中EB病毒转录的核内小RNA(EBV encoded small RNAs, EBER)的免疫反应。秩和检验统计学方法分析鼻咽癌和慢性鼻咽炎鼻咽组织之间EB病毒免疫反应强度的差异。
结果：
(1)在鼻咽癌患者鼻咽部组织中观测到严重程度的DNA损伤。57例鼻咽癌组织细胞中8-NitroG、8-OHdG和iNOS均为强免疫反应,8-NitroG、8-OHdG阳性率100%,iNOS阳性率94.7%,与39例慢性鼻咽炎组织比较差异显著(P＜0.05)。
(2)36例鼻咽癌患者血清中8-OHdG的平均水平为0.538±0.336ng/ml,而对照组中36例健康人的血清中8-OHdG的平均水平为0.069±0.059ng/ml,鼻咽癌患者血清中8-OHdG水平与健康人比较差异显著(P＜0.05)。
(3)在鼻咽癌患者鼻咽部组织中观测到p-Stat3及EGFR强烈的免疫反应。鼻咽癌组织细胞中p-Stat3及EGFR观察到强免疫反应,p-Stat3、EGFR阳性率均为94.7%,与39例慢性鼻咽炎组织比较差异显著(P＜0.05)。
(4)在鼻咽癌患者鼻咽部组织中观测到CD68、IL-6强烈的免疫反应。57例鼻咽癌组织细胞中CD68、IL-6均为强免疫反应,CD68、IL-6阳性率100%,与39例慢性鼻咽炎组织比较差异显著(P＜0.05)。
(5)在鼻咽癌患者鼻咽部组织中观测到EBER强烈的反应。57例鼻咽癌组织细胞中EBER阳性率100%,均为EB病毒阳性,与39例慢性鼻咽炎组织比较差异显著(P＜0.05)。
结论：
(1)鼻咽癌组织中有氧化性DNA损伤存在。
(2)氧化性DNA损伤与iNOS的高表达有关。
(3)鼻咽部组织中由于细菌、病毒及寄生虫等引起的炎症反应等病理性刺激,可能会导致诱导型一氧化氮合酶(iNOS)催化产生一氧化氮(nitric oxide, NO),进而产生硝基化及氧化性DNA损伤,导致鼻咽癌的发生和发展。iNOS的高表达可能是由于EB病毒LMP1通过TRAFs上调EGFR表达,EGFR与特定配体EGF或TGF-a结合后,导致细胞内受体区自我磷酸化,并利用其本身的酪氨酸激酶活性活化Stat3 (p-Stat3),从而促进iNOS基因表达。诱导iNOS高表达的另一通路还可能是由于EB病毒作为抗原存在于鼻咽上皮细胞,导致鼻咽部巨噬细胞、T和B淋巴细胞、血管平滑肌细胞和中性粒细胞的聚集并分泌炎性细胞因子如IL-6,通过IL-6/gp130/Jak途径激活Stat3 (p-Stat3),p-Stat3促进iNOS基因表达。由于iNOS的高表达,细胞内NO活性氧增加,通过NO引起DNA损伤,最后诱发癌变。
(4) 8-NitroG、8-OHdG有望成为辅助诊断鼻咽癌的一个生物标志物。更好的理解鼻咽癌中氧化性DNA损伤的作用机制可以为通过分子水平调节炎症的过程以达到癌症预防的目的提供一个新的研究策略。
Purpose:
The oxidative nucleotide bases in tissues and serum were examined separately using double immunofluorescent staining and ELISA method.The status of EB virus infections in the tissues of NPC was examined useing fluorescence in situ hybridization (FISH). Preliminarily to explore that whether the origination and development of the NPC are related to the oxidative DNA damage, in order to find out the potential biomarkers for the diagnose of NPC.
Methods:
(1) 57 cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine the expression of iNOS, the formation of 8-NitroG and 8-OHdG using double immunofluorescent staining. The statistical differences in immunoreactivities were analyzed using a Mann-Whitney test.
(2) 36 patients from 57 cases with NPC and a group of 36 noncancer controls were investigated to examine the level of serum 8-OHdG using enzyme-linked immunosorbent assay (ELISA) method. The statistical differences were analyzed using a t test.
(3) 57 cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine the expression of phosphorylated signal transducers and activators of transcription (p-Stat3) and epidermal growth factor receptor (EGFR), using double immunofluorescent staining. The statistical differences in immunoreactivities were analyzed using a Mann-Whitney test.
(4) 57 cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine CD68, the surface antigen of macrophages and its expression product interleukin-6 (IL-6), using double immunofluorescent staining. The statistical differences in immunoreactivities were analyzed using a Mann-Whitney test.
(5) 57 cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine EBV encoded small RNAs (EBER), using fluorescent in situ hybridization (FISH). The statistical differences in immunoreactivities were analyzed using a Mann-Whitney test.
Results:
(1) Strong DNA lesions were observed in cancer cells of NPC patients. 8-NitroG and 8-OHdG were positive, observed in all cases of NPC (100%). iNOS was observed in fifty-four cases of NPC (94.7%). Samples from NPC exhibited significantly more intense staining for 8-NitroG,8-OHdG and iNOS than those of chronic nasopharyngitis (P<0.05).
(2) The mean value of serum 8-OHdG level of thirty-six NPC patients was 0.538±0.336ng/ml compared to 0.069±0.059ng/ml of thirty-six noncancer controls. The difference of 8-OHdG levels in serum of NPC patients and noncancer controls was statistically significant (P<0.05).
(3) P-Stat3 and EGFR were positive, both observed in fifty-four cases of NPC (94.7%). Samples from NPC exhibited significantly more intense staining for P-State3 and EGFR than those of chronic nasopharyngitis (P<0.05).
(4)CD68 and IL-6 were positive, observed in all cases of NPC (100%). Samples from NPC exhibited significantly more intense staining for CD68 and IL-6 than those of chronic nasopharyngitis (P<0.05).
(5) EBER was positive, observed in all cases of NPC (100%). Samples from NPC exhibited significantly more intense staining for EBER than those of chronic nasopharyngitis (P<0.05).
Conclusions:
(1)The oxidative DNA damage exists in NPC.
(2) The oxidative DNA damage was related to the up-regulation of iNOS.
(3) The pathological stimulations, such as inflammations from the bacteria, virus and parasite in nasopharyngeal tissues, might lead to nitrative and oxidative DNA lesions by iNOS catalyzed NO, which contribute to the origination and development of NPC. The high expression of iNOS was possibly because of the up-regulation of EGFR owing to TRAFs expression by LMP1. Combining of EGFR and specific ligand EGF or TGF-a union causes the acceptor area self-phosphorylation in the cell and activates Stat3 using its tyrosine activating enzyme activeness. Another circuit of up-regulation of iNOS possibly was because the EB virus exists as the antigen in the nasopharynx epithelial cell, causing the accumulation of nasopharynx department macrophage, T and the B lymphocyte, the blood vessel smooth muscle cell and the neutral granular cell,which secretes inflammatory cell factor like IL-6. p-Stat3 was activated through IL-6/gp130/the Jak pathway. p-Stat3 promotes the iNOS gene expression. As a result of the iNOS high expression, in the cell the NO active oxygen increasing, causes the DNA damage through NO, which finally induces the cancer.
(4) 8-NitroG and 8-OHdG could be suitable and promising biomarkers for evaluating the risk of NPC. Better understanding of the mechanisms and role of such nitrative and oxidative DNA damage in NPC is a necessary basis to develop new strategies for cancer prevention by modulating the process of inflammation.
运用双色免疫荧光组织化学方法以及酶联免疫吸附试验分别检测鼻咽癌鼻咽组织及血清中氧化性DNA损伤的情况,并且运用荧光原位杂交技术检测鼻咽癌组织中EB病毒感染的情况,初步探索鼻咽癌的发生和发展是否与氧化性DNA损伤有关及其损伤的可能原因和途径,以期寻找出能够辅助鼻咽癌诊断的生物标志物。
方法：
(1)选择57例鼻咽癌患者和39例慢性鼻咽炎患者鼻咽部组织,采用双色免疫荧光组织化学方法分别检测8-硝基鸟嘌呤(8-nitroguanine, 8-NitroG),8-羟基脱氧鸟苷(8-hydroxy-2'-deoxyguanosine,8-OHdG)和诱导型一氧化氮合酶(inducible nitric oxide synthase, iNOS)的免疫反应。秩和检验统计学方法分析鼻咽癌和慢性鼻咽炎鼻咽组织之间8-NitroG、8-OHdG和iNOS免疫反应强度的差异。
(2)从57例鼻咽癌中随机选择36例鼻咽癌患者和36例健康人血清标本,采用酶联免疫吸附试验方法(enzyme-linked immunosorbent assay, ELISA)检测血清中8-羟基脱氧鸟苷(8-OHdG)的表达水平。采用成组t检验进行数据的统计学分析。
(3)选择57例鼻咽癌患者和39例慢性鼻咽炎患者鼻咽部组织,采用双色免疫荧光组织化学方法分别检测磷酸化的信号转导及转录激活因子(phosphorylated signal transducers and activators of transcription, p-Stat3),表皮生长因子受体(epidermal growth factor receptor, EGFR)的免疫反应。秩和检验统计学方法分析鼻咽癌和慢性咽炎鼻咽组织之间p-Stat3.EGFR免疫反应强度的差异。
(4)选择57例鼻咽癌患者和39例慢性鼻咽炎患者鼻咽部组织,采用双色免疫荧光组织化学方法分别检测鼻咽癌组织中巨噬细胞的表面抗原CD68及其表达产物IL-6的免疫反应。秩和检验统计学方法分析鼻咽癌和慢性鼻咽炎鼻咽组织之间CD68、IL-6免疫反应强度的差异。
(5)选择57例鼻咽癌患者和39例慢性鼻咽炎患者鼻咽部组织,采用荧光原位杂交法(fluorescent in situ hybridization, FISH)检测鼻咽癌组织中EB病毒转录的核内小RNA(EBV encoded small RNAs, EBER)的免疫反应。秩和检验统计学方法分析鼻咽癌和慢性鼻咽炎鼻咽组织之间EB病毒免疫反应强度的差异。
结果：
(1)在鼻咽癌患者鼻咽部组织中观测到严重程度的DNA损伤。57例鼻咽癌组织细胞中8-NitroG、8-OHdG和iNOS均为强免疫反应,8-NitroG、8-OHdG阳性率100%,iNOS阳性率94.7%,与39例慢性鼻咽炎组织比较差异显著(P＜0.05)。
(2)36例鼻咽癌患者血清中8-OHdG的平均水平为0.538±0.336ng/ml,而对照组中36例健康人的血清中8-OHdG的平均水平为0.069±0.059ng/ml,鼻咽癌患者血清中8-OHdG水平与健康人比较差异显著(P＜0.05)。
(3)在鼻咽癌患者鼻咽部组织中观测到p-Stat3及EGFR强烈的免疫反应。鼻咽癌组织细胞中p-Stat3及EGFR观察到强免疫反应,p-Stat3、EGFR阳性率均为94.7%,与39例慢性鼻咽炎组织比较差异显著(P＜0.05)。
(4)在鼻咽癌患者鼻咽部组织中观测到CD68、IL-6强烈的免疫反应。57例鼻咽癌组织细胞中CD68、IL-6均为强免疫反应,CD68、IL-6阳性率100%,与39例慢性鼻咽炎组织比较差异显著(P＜0.05)。
(5)在鼻咽癌患者鼻咽部组织中观测到EBER强烈的反应。57例鼻咽癌组织细胞中EBER阳性率100%,均为EB病毒阳性,与39例慢性鼻咽炎组织比较差异显著(P＜0.05)。
结论：
(1)鼻咽癌组织中有氧化性DNA损伤存在。
(2)氧化性DNA损伤与iNOS的高表达有关。
(3)鼻咽部组织中由于细菌、病毒及寄生虫等引起的炎症反应等病理性刺激,可能会导致诱导型一氧化氮合酶(iNOS)催化产生一氧化氮(nitric oxide, NO),进而产生硝基化及氧化性DNA损伤,导致鼻咽癌的发生和发展。iNOS的高表达可能是由于EB病毒LMP1通过TRAFs上调EGFR表达,EGFR与特定配体EGF或TGF-a结合后,导致细胞内受体区自我磷酸化,并利用其本身的酪氨酸激酶活性活化Stat3 (p-Stat3),从而促进iNOS基因表达。诱导iNOS高表达的另一通路还可能是由于EB病毒作为抗原存在于鼻咽上皮细胞,导致鼻咽部巨噬细胞、T和B淋巴细胞、血管平滑肌细胞和中性粒细胞的聚集并分泌炎性细胞因子如IL-6,通过IL-6/gp130/Jak途径激活Stat3 (p-Stat3),p-Stat3促进iNOS基因表达。由于iNOS的高表达,细胞内NO活性氧增加,通过NO引起DNA损伤,最后诱发癌变。
(4) 8-NitroG、8-OHdG有望成为辅助诊断鼻咽癌的一个生物标志物。更好的理解鼻咽癌中氧化性DNA损伤的作用机制可以为通过分子水平调节炎症的过程以达到癌症预防的目的提供一个新的研究策略。
Purpose:
The oxidative nucleotide bases in tissues and serum were examined separately using double immunofluorescent staining and ELISA method.The status of EB virus infections in the tissues of NPC was examined useing fluorescence in situ hybridization (FISH). Preliminarily to explore that whether the origination and development of the NPC are related to the oxidative DNA damage, in order to find out the potential biomarkers for the diagnose of NPC.
Methods:
(1) 57 cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine the expression of iNOS, the formation of 8-NitroG and 8-OHdG using double immunofluorescent staining. The statistical differences in immunoreactivities were analyzed using a Mann-Whitney test.
(2) 36 patients from 57 cases with NPC and a group of 36 noncancer controls were investigated to examine the level of serum 8-OHdG using enzyme-linked immunosorbent assay (ELISA) method. The statistical differences were analyzed using a t test.
(3) 57 cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine the expression of phosphorylated signal transducers and activators of transcription (p-Stat3) and epidermal growth factor receptor (EGFR), using double immunofluorescent staining. The statistical differences in immunoreactivities were analyzed using a Mann-Whitney test.
(4) 57 cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine CD68, the surface antigen of macrophages and its expression product interleukin-6 (IL-6), using double immunofluorescent staining. The statistical differences in immunoreactivities were analyzed using a Mann-Whitney test.
(5) 57 cases of NPC and 39 cases of chronic nasopharyngitis were investigated to examine EBV encoded small RNAs (EBER), using fluorescent in situ hybridization (FISH). The statistical differences in immunoreactivities were analyzed using a Mann-Whitney test.
Results:
(1) Strong DNA lesions were observed in cancer cells of NPC patients. 8-NitroG and 8-OHdG were positive, observed in all cases of NPC (100%). iNOS was observed in fifty-four cases of NPC (94.7%). Samples from NPC exhibited significantly more intense staining for 8-NitroG,8-OHdG and iNOS than those of chronic nasopharyngitis (P<0.05).
(2) The mean value of serum 8-OHdG level of thirty-six NPC patients was 0.538±0.336ng/ml compared to 0.069±0.059ng/ml of thirty-six noncancer controls. The difference of 8-OHdG levels in serum of NPC patients and noncancer controls was statistically significant (P<0.05).
(3) P-Stat3 and EGFR were positive, both observed in fifty-four cases of NPC (94.7%). Samples from NPC exhibited significantly more intense staining for P-State3 and EGFR than those of chronic nasopharyngitis (P<0.05).
(4)CD68 and IL-6 were positive, observed in all cases of NPC (100%). Samples from NPC exhibited significantly more intense staining for CD68 and IL-6 than those of chronic nasopharyngitis (P<0.05).
(5) EBER was positive, observed in all cases of NPC (100%). Samples from NPC exhibited significantly more intense staining for EBER than those of chronic nasopharyngitis (P<0.05).
Conclusions:
(1)The oxidative DNA damage exists in NPC.
(2) The oxidative DNA damage was related to the up-regulation of iNOS.
(3) The pathological stimulations, such as inflammations from the bacteria, virus and parasite in nasopharyngeal tissues, might lead to nitrative and oxidative DNA lesions by iNOS catalyzed NO, which contribute to the origination and development of NPC. The high expression of iNOS was possibly because of the up-regulation of EGFR owing to TRAFs expression by LMP1. Combining of EGFR and specific ligand EGF or TGF-a union causes the acceptor area self-phosphorylation in the cell and activates Stat3 using its tyrosine activating enzyme activeness. Another circuit of up-regulation of iNOS possibly was because the EB virus exists as the antigen in the nasopharynx epithelial cell, causing the accumulation of nasopharynx department macrophage, T and the B lymphocyte, the blood vessel smooth muscle cell and the neutral granular cell,which secretes inflammatory cell factor like IL-6. p-Stat3 was activated through IL-6/gp130/the Jak pathway. p-Stat3 promotes the iNOS gene expression. As a result of the iNOS high expression, in the cell the NO active oxygen increasing, causes the DNA damage through NO, which finally induces the cancer.
(4) 8-NitroG and 8-OHdG could be suitable and promising biomarkers for evaluating the risk of NPC. Better understanding of the mechanisms and role of such nitrative and oxidative DNA damage in NPC is a necessary basis to develop new strategies for cancer prevention by modulating the process of inflammation.
引文
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