气虚体质状态与二亚硝基哌嗪相互作用致鼻咽癌前病变机制研究
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摘要
鼻咽癌在我国南方与东南亚地区相对高发。为了解中医体质在鼻咽癌前病变启动、发展过程中作用,本课题从四个方面探讨了中医气虚体质状态与环境因素相互作用导致鼻咽癌前病变的机制。
1.EB病毒IgA/VCA不同滴度的中医体质类型分布特征:从中山市中医院耳鼻咽喉科门诊784名就诊病人中,遴选出150名就诊者作为调查对象。诊断出调查对象的中医体质并对其进行血清IgA/VCA检测,通过统计学分析,确定EBV不同感染程度人群的中医体质分布特征。结果显示在感染和重感染人群中,气虚体质所占比例明显比其他体质高(P＜0.05),而正常体质、失调湿质明显低于其他体质人群(P＜0.05)。
2.气虚造模大鼠鼻咽上皮组织后续性变化基因表达谱特征:雄性4周龄SD大鼠,力竭游泳造模100天后,将大鼠鼻咽上皮组织制备成组织匀浆,酶标仪比色,检测大鼠鼻咽上皮组织MDA含量、SOD酶活力。气虚组与益气中药干预组、空白对照组比较,力竭游泳时间明显缩短(P＜0.05);气虚组鼻咽上皮组织MDA含量和SOD活力与益气中药干预组、空白对照组比较,MDA含量显著增高,SOD活力明显下降。提取气虚组和空白对照组鼻咽上皮组织总RNA,探针标记与杂交后,荧光扫描,建立双色荧光标记叠加图和杂交信号强度散点图。共筛选出差异表达基因117条。下调的基因中,白介素-1β及其相关基因差异最显著;谷胱甘肽-S-转移酶相关基因GstaW1、GstaW2表达上调,谷胱甘肽合成酶表达下调。
3.气虚体质与二亚硝基哌嗪相互作用致大鼠鼻咽组织上皮细胞微观病理变化及黄芪、黄连复方有效成分的干预:SD大鼠通过力竭游泳和DNP诱癌及益气解毒中药干预200天后,取鼻咽组织做常规病理观察和电镜观察。力竭游泳+DNP诱癌组比单纯DNP诱癌组鼻咽癌前病变例数显著增多(P＜0.05)。而益气解毒复方有效成分能明显减低力竭游泳和DNP相互作用的诱癌率(P＜0.05)。
4.气虚体质与DNP相互作用致大鼠鼻咽癌前病变相关蛋白筛选和鉴定:雄性SD大鼠力竭游泳和DNP诱癌后,选取具有明显癌前病变趋势的大鼠和正常大鼠鼻咽组织,分别提取总蛋白,进行双向电泳后,考马斯蓝染色,PDQuest软件分析2-DE图像,并对差异蛋白进行生物信息学分析鉴定。筛选出9个与肿瘤发生可能有联系的表达上调蛋白,涉及细胞周期调控、细胞蛋白质转运、能量代谢、细胞粘附连接等多个分子事件。
结果提示,气虚体质状态可能是环境致癌物DNP的敏感体质状态,其对DNP诱癌敏感性提高的分子基础,可能是谷胱甘肽-S-转移酶基因表达异常和白介素-1β相关基因表达下调。气虚状态与DNP相互作用而启动鼻咽癌前病变的机制复杂,可能涉及多个分子事件。
Nasopharyngeal carcinoma (NPC) is the most commonly seen malignancy in the region of head and neck in southern China and Southeast Asia and closely related with precanceron lesion in the nasopharynx in its iniation and development. In order to investigate the possible role of Qi-dificient physique status in the pathogenesis underlying of nasopharyngeal precancerous lesions, the interactive effects of such a status of physique with environmental factor on this pathologic process were carried out in the following four aspects.
Firstly, a survey was made to explore the distributing characteristic of the physique types in the terms of Traditional Chinese Medicine (TCM) in the population with various titers of EB virus associated antibody IgA/VCA. 150 cases were sampled from 784 persons consulting at the out-pationt clinic of Zhongshan TCM Hospital as the surveying object. Then, IgA/VCA titers in serum were determined and the types of physique status were investigated among them to analyze the distribution characteristics of the physique types in population with EBV infection and their association with EBV infecting activity as indicated by the level of IgA/VCA. The results showed that the rate of cases with a physique type of Qi-deficiency was significantly higher than that of other types of physique status (P<0.05) and normal physique status and imbalanced mixed with dampness were significant lower than other types (P<0.05) among this sample of population.
Secondly, experiment was carried out to explore the delayed changing features in gene expressive profile of nasopharyngeal tissues among rats following Qi-deficiency modeling for a longer period. Male SD rats at the age of 4 weeks were modeled by exhausted swimming method in a deep pool, one time a day and lasted for 30 days, and the tissue samples of nasopharyngeal mucosa were taken 100 days late from them. Then, the total RNA was extracted from the tissue samples by hybridization was made with probe. Followed was fluorescence scanning and signal analysis to screen the differentially expressed gene in these samples. As a result of these procedures, 117 genes were detected as differentially expressed genes, with 41 up-regulated and 76 down regulated. Among those down regulated in their expressed activity, the most significance expressing genes were IL-1βand its related genes. Moreover, the expression of GstaW1 and GstaW2 genes were upregulated and that of Gsta synthesize enzyme gene was down regulated.
Thirdly, studies were made to investigate the interactive effects of Qi-deficient physique status with N, N'-dinitrosopiperazine (DNP ) on the ultrastructural pathology of lesion of nasopharyngeal mucosa among rats with precancerom in the imitation and development of the nasopharyngeal mucosa, and the intervening effects of compound components extracted from astragalus and coptis on this lesion induced by such an intervention effect. Two hundred days late following exhausted swimming to induce Qi-deficiency and DNP injection to induce nasopharyngeal carcinoma genesis in a combined way and intervening with components extracted from Qi-boosting toxin-eliminating herbal medicines, nasopharyngeal mucosa was taken from the experimental animals and tissues samples were cut to do light and electronic microscopies respectindy in order to evaluated the pathohistological differences among these groups of animals. The results indicated that significantly increased number of animals with precancerous nasopharyngeal lesion was seen in the modeling group induced by exhausted swimming plus DNP using and markedly fewer number of animals with this kind of lesion was confirmed in the group simply using DNP to induce such a lesion (p<0.05).
Fourthly, proteomic study was performed to screen and identify the associated proteins with the imitation and development of nasopharyngeal precancerous lesions among the animals affected of Qi-dificient status and DNP induced carcinogenesis among mile SD rats and determination of ultrastructural pathology on nasopharyngeal precancerous lesions among them, nasopharyngeal tissue samples were respectively taken from healthy control animals and ones with most significant precancerous lesion in the nasopharynx to extract the total cellular protein for electrophoresis in two dimensions(2-DE). Then, the gels were stained by Comas blue and analyzed by PDQuest software, with a match of normal nasopharyngeal tissue with that of precancerous lesions made on the dots of 2-DE gels. After this step, bio-informatics analysis was carried out to screen and identify the differentially expressed in the nasopharyngeal mucosa with precancerous lesion, 9 up-regulated protein were screened out, with a possible association in carcinogenesis, mainly invoking such molecular events as cell cycle regulation, protein transportation, energy metabolism, cellular adhesion and junction etc..
In summary, Qi-deficient physique status is one physique status sensitive to environmental cancer-inducing materials such as DNP. This elevated sensitivity to cancer inducing effect by DNP suggested a molecular basis responsible for the precancerous lesion in the nasopharynx, possibly associated closely with the abnormal expression of Gsta genes and up regulated expression of IL-1βrelated genes. The interactive effects of Qi-deficient physique status with DNP using may iniciate the progressing process of nasopharyngeal precancerous lesions, causing very complex events in the signaling network take place underlying the carcinogenesis and involving lots of molecular events in this process.
1.EB病毒IgA/VCA不同滴度的中医体质类型分布特征:从中山市中医院耳鼻咽喉科门诊784名就诊病人中,遴选出150名就诊者作为调查对象。诊断出调查对象的中医体质并对其进行血清IgA/VCA检测,通过统计学分析,确定EBV不同感染程度人群的中医体质分布特征。结果显示在感染和重感染人群中,气虚体质所占比例明显比其他体质高(P＜0.05),而正常体质、失调湿质明显低于其他体质人群(P＜0.05)。
2.气虚造模大鼠鼻咽上皮组织后续性变化基因表达谱特征:雄性4周龄SD大鼠,力竭游泳造模100天后,将大鼠鼻咽上皮组织制备成组织匀浆,酶标仪比色,检测大鼠鼻咽上皮组织MDA含量、SOD酶活力。气虚组与益气中药干预组、空白对照组比较,力竭游泳时间明显缩短(P＜0.05);气虚组鼻咽上皮组织MDA含量和SOD活力与益气中药干预组、空白对照组比较,MDA含量显著增高,SOD活力明显下降。提取气虚组和空白对照组鼻咽上皮组织总RNA,探针标记与杂交后,荧光扫描,建立双色荧光标记叠加图和杂交信号强度散点图。共筛选出差异表达基因117条。下调的基因中,白介素-1β及其相关基因差异最显著;谷胱甘肽-S-转移酶相关基因GstaW1、GstaW2表达上调,谷胱甘肽合成酶表达下调。
3.气虚体质与二亚硝基哌嗪相互作用致大鼠鼻咽组织上皮细胞微观病理变化及黄芪、黄连复方有效成分的干预:SD大鼠通过力竭游泳和DNP诱癌及益气解毒中药干预200天后,取鼻咽组织做常规病理观察和电镜观察。力竭游泳+DNP诱癌组比单纯DNP诱癌组鼻咽癌前病变例数显著增多(P＜0.05)。而益气解毒复方有效成分能明显减低力竭游泳和DNP相互作用的诱癌率(P＜0.05)。
4.气虚体质与DNP相互作用致大鼠鼻咽癌前病变相关蛋白筛选和鉴定:雄性SD大鼠力竭游泳和DNP诱癌后,选取具有明显癌前病变趋势的大鼠和正常大鼠鼻咽组织,分别提取总蛋白,进行双向电泳后,考马斯蓝染色,PDQuest软件分析2-DE图像,并对差异蛋白进行生物信息学分析鉴定。筛选出9个与肿瘤发生可能有联系的表达上调蛋白,涉及细胞周期调控、细胞蛋白质转运、能量代谢、细胞粘附连接等多个分子事件。
结果提示,气虚体质状态可能是环境致癌物DNP的敏感体质状态,其对DNP诱癌敏感性提高的分子基础,可能是谷胱甘肽-S-转移酶基因表达异常和白介素-1β相关基因表达下调。气虚状态与DNP相互作用而启动鼻咽癌前病变的机制复杂,可能涉及多个分子事件。
Nasopharyngeal carcinoma (NPC) is the most commonly seen malignancy in the region of head and neck in southern China and Southeast Asia and closely related with precanceron lesion in the nasopharynx in its iniation and development. In order to investigate the possible role of Qi-dificient physique status in the pathogenesis underlying of nasopharyngeal precancerous lesions, the interactive effects of such a status of physique with environmental factor on this pathologic process were carried out in the following four aspects.
Firstly, a survey was made to explore the distributing characteristic of the physique types in the terms of Traditional Chinese Medicine (TCM) in the population with various titers of EB virus associated antibody IgA/VCA. 150 cases were sampled from 784 persons consulting at the out-pationt clinic of Zhongshan TCM Hospital as the surveying object. Then, IgA/VCA titers in serum were determined and the types of physique status were investigated among them to analyze the distribution characteristics of the physique types in population with EBV infection and their association with EBV infecting activity as indicated by the level of IgA/VCA. The results showed that the rate of cases with a physique type of Qi-deficiency was significantly higher than that of other types of physique status (P<0.05) and normal physique status and imbalanced mixed with dampness were significant lower than other types (P<0.05) among this sample of population.
Secondly, experiment was carried out to explore the delayed changing features in gene expressive profile of nasopharyngeal tissues among rats following Qi-deficiency modeling for a longer period. Male SD rats at the age of 4 weeks were modeled by exhausted swimming method in a deep pool, one time a day and lasted for 30 days, and the tissue samples of nasopharyngeal mucosa were taken 100 days late from them. Then, the total RNA was extracted from the tissue samples by hybridization was made with probe. Followed was fluorescence scanning and signal analysis to screen the differentially expressed gene in these samples. As a result of these procedures, 117 genes were detected as differentially expressed genes, with 41 up-regulated and 76 down regulated. Among those down regulated in their expressed activity, the most significance expressing genes were IL-1βand its related genes. Moreover, the expression of GstaW1 and GstaW2 genes were upregulated and that of Gsta synthesize enzyme gene was down regulated.
Thirdly, studies were made to investigate the interactive effects of Qi-deficient physique status with N, N'-dinitrosopiperazine (DNP ) on the ultrastructural pathology of lesion of nasopharyngeal mucosa among rats with precancerom in the imitation and development of the nasopharyngeal mucosa, and the intervening effects of compound components extracted from astragalus and coptis on this lesion induced by such an intervention effect. Two hundred days late following exhausted swimming to induce Qi-deficiency and DNP injection to induce nasopharyngeal carcinoma genesis in a combined way and intervening with components extracted from Qi-boosting toxin-eliminating herbal medicines, nasopharyngeal mucosa was taken from the experimental animals and tissues samples were cut to do light and electronic microscopies respectindy in order to evaluated the pathohistological differences among these groups of animals. The results indicated that significantly increased number of animals with precancerous nasopharyngeal lesion was seen in the modeling group induced by exhausted swimming plus DNP using and markedly fewer number of animals with this kind of lesion was confirmed in the group simply using DNP to induce such a lesion (p<0.05).
Fourthly, proteomic study was performed to screen and identify the associated proteins with the imitation and development of nasopharyngeal precancerous lesions among the animals affected of Qi-dificient status and DNP induced carcinogenesis among mile SD rats and determination of ultrastructural pathology on nasopharyngeal precancerous lesions among them, nasopharyngeal tissue samples were respectively taken from healthy control animals and ones with most significant precancerous lesion in the nasopharynx to extract the total cellular protein for electrophoresis in two dimensions(2-DE). Then, the gels were stained by Comas blue and analyzed by PDQuest software, with a match of normal nasopharyngeal tissue with that of precancerous lesions made on the dots of 2-DE gels. After this step, bio-informatics analysis was carried out to screen and identify the differentially expressed in the nasopharyngeal mucosa with precancerous lesion, 9 up-regulated protein were screened out, with a possible association in carcinogenesis, mainly invoking such molecular events as cell cycle regulation, protein transportation, energy metabolism, cellular adhesion and junction etc..
In summary, Qi-deficient physique status is one physique status sensitive to environmental cancer-inducing materials such as DNP. This elevated sensitivity to cancer inducing effect by DNP suggested a molecular basis responsible for the precancerous lesion in the nasopharynx, possibly associated closely with the abnormal expression of Gsta genes and up regulated expression of IL-1βrelated genes. The interactive effects of Qi-deficient physique status with DNP using may iniciate the progressing process of nasopharyngeal precancerous lesions, causing very complex events in the signaling network take place underlying the carcinogenesis and involving lots of molecular events in this process.
引文
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[5]湖南医学院肿瘤研究室.亚硝胺类化合物诱发大鼠鼻咽癌的实验研究.科学通报;1978,23(12):756-769
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[9]王水良,贺智敏,朱建华,侯德富,陈主初.人CYP4502E1异源性表达模型的建立及底物的表达诱导作用.中国病理生理杂志,2004;20(2):166-169
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