TgN（p53mt-LMP1）/HT小鼠鼻咽上皮细胞间隙连接与鼻咽上皮细胞癌变的相关性及益气解毒方的干预效应
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摘要
本研究分二部分完成。
第一部分TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞间隙连接结构特征及其与鼻咽黏膜上皮细胞癌前病变的关系
目的：明确TgN(p53mt-LMP1)/HT小鼠鼻咽上皮细胞癌变与细胞间隙连接通讯的关系。方法：G10代模型鼠按12、15、18月龄随机分为3组,每组各12只。每组另设同品系健康野生小鼠为对照组,每组12只。观察不同月龄转基因小鼠鼻咽黏膜上皮细胞超微病理学特征与细胞间隙连接变化;用免疫组化、Western-blot法、RT-PCR技术检测Cx43、Cx32、Cx26及其mRNA的表达水平；并对各蛋白表达水平进行相关性分析。结果：TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞异型性改变随月龄增加而呈现加重趋势；细胞核、线粒体形态发生改变,细胞间隙增宽,细胞连接明显减少或缺失,连接长度缩短,对照组无相应改变。各月龄转基因小鼠鼻咽黏膜Cx43、Cx32、Cx26及其mRNA表达水平随月龄增长而呈现下降趋势。其中15月、18月龄转基因小鼠鼻咽上皮细胞Cx43、Cx32、Cx26蛋白表达水平明显低于12月龄转基因小鼠,差异有统计学意义(P值均小于0.05)；15月龄、18月龄小鼠鼻咽上皮细胞Cx43、Cx32、Cx26蛋白表达水平无显著性差异(P>0.05)。各月龄转基因小鼠鼻咽黏膜上皮细胞Cx43、Cx32、Cx26及其mRNA表达水平均低于同月龄野生小鼠,差异均有统计学意义(P<0.05或P<0.01)。对各月龄转基因鼠Cx43、Cx32、Cx26表达水平关联性进行分析,发现Cx43-Cx32、Cx43-Cx26、Cx32-Cx26呈正相关(P<0.05)。
结论：TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞异型性改变随时间增长而加重,细胞间隙增宽,细胞连接明显减少或缺失,连接长度缩短可能与Cx43、Cx32、Cx26及其mRNA表达水平下降,细胞间隙连接通讯功能障碍有关。
第二部分益气解毒方对TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞间隙连接通讯的干预效应及其对鼻咽黏膜上皮细胞癌前病变发展过程的影响
目的：研究益气解毒方对TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞间隙连接通讯的干预效应及其对鼻咽上皮细胞癌变过程的影响。方法：模型鼠72只随机分为3组,模型组[(modeling group, MG),每天灌胃生理盐水0.2ml]、益气解毒方干预组[(Qi-boosting toxin-resolving intervening group, QG),每天灌胃益气解毒方剂0.2ml]、维A酸阳性对照组[(Tretinoin positive controlling group, TG),每天灌胃维A酸药剂0.2ml]；同品系健康野生鼠24只作阴性对照组(Natural group, NG),不另加其他干预因素。各组均用诱癌剂二亚硝基哌嗪(N, N'-dinitrosopiperazine, DNP)进行处理,以100mg/kg体重皮下注射,每周2次,共计28次,共处理14周,但不应用促癌剂佛波醇酯((12-O-tetradecanoylphorbol, TPA)。观察各组小鼠鼻咽黏膜组织病理学、超微病理学特征与细胞间隙连接变化；用免疫组化、Western-blot法、RT-PCR技术检测Cx43、Cx32、Cx26及其mRNA的表达水平。结果：MG组鼻咽黏膜上皮细胞异型性增生明显,有癌变特征,TG组、QG组鼻咽黏膜上皮细胞表现轻度异型增生,NG组部分鼻咽黏膜上皮细胞呈单纯性增生。MG组细胞膜呈伪足样改变,细胞核形态异常,核切迹增多,线粒体肿胀肥大或透明变性,乃至空泡状,细胞间隙增宽,细胞连接明显减少或缺失,连接长度缩短,TG组、NG组、QG组无上述改变。MG组Cx43、Cx32、Cx26及其mRNA表达水平显著低于TG组、NG组、QG组(P<0.05和P<0.01),而QG组上述蛋白及其mRNA表达量显著高于其在MG组和TG组中的表达水平(P<0.05)。结论：益气解毒方逆转鼻咽黏膜上皮细胞癌前病变的发展,可能通过恢复细胞间隙连接通讯功能,抑制细胞增殖,诱导细胞凋亡而实现。GJIC已成为肿瘤预防和治疗研究的潜在靶点之一。
This paper is composed of following two parts.
PART ONE Gap junctional intercellular characteristics in nasopharyngeal epithelia of TgN(p53mt-LMP1)/HT transgenic mice and its association with the precancerous lesion in nasopharyngeal epithelia
Objective:To investigate the characteristics of GJIC in nasopharyngeal epithelia of TgN(p53mt-LMP1)/HTcorrelation and its association with the precancerous lesion in nasopharyngeal epithelia.
Methods:Included in this part of study were 36 animals randomly chosen from the generation of G10 TgN(p53mt-LMP1)/HT transgenic mice at the month age of 12th,15th and 18th respectively with positively expressed p53 and LMP1 activities, divided into 3 groups with 12 mice in each. Another 3 groups of wild mice in the same strain were taken as the negative control group, with the same age animals in each group and at the same month age as well respectively. Then, their nasopharyngeal mucosa membrane was taken to prepare tissue samples. The morphological changes and cell gap junction of nasopharyngeal epithelia were observed under light microscope and transmission electronic microscope at the same time. The expressive activities of Cx43, Cx32, Cx26 proteins and their responsible mRNA were detected by immunohistochemistry, western blot and reverse transcription polymerase chain reaction (RT-PCR), respectively.
Results:An obviously increased tendency of precancerous lesions in the nasopharyngeal epithelia of TgN(p53mt-LMP1)/HT transgenic mice was shown with the increase of the age, and the shape of nuclear and mitochondrial was abnormal as shown by the electronic microscopy. Meanwhile, the increased intercellular space, reduced cell junction length and decreased cell junction number were observed obviously, with the increasing of the age. There was a decreasing tendency seen in the expressive activities of Cx43, Cx32, Cx26 proteins and their responsible mRNA in these tissue samples. The expression of Cx43, Cx32, Cx26 proteins in the animals at the age of 15th and 18th was significantly lower than those at the age of 12th month (P<0.05). There was no statistical significance of the expression of Cx43, Cx32, Cx26 proteins and their responsible mRNA in the transgenic mice at the age of 15th and 18th(P> 0.05). The expression level of Cx43,Cx32,Cx26 protein and mRNA were decreased significantly compared with the wild groups at the same age (P<0.05). The correlation anlysis of Cx43,Cx32,Cx26 of the groups of the transgenics mice: Cx43-Cx32, Cx43-Cx26, Cx32-Cx26 were positive correlation (P<0.05).
Conclusions:It can be concluded that the developing process of precancerous lesion in nasopharyngeal epithelia was possibly associated with the decreased expressive activity of Cx43, Cx32, Cx26 proteins and their responsible mRNA. Indeed, the carcinogenesis of nasopharyngeal epithelia of TgN (p53mt-LMP1)/ HT transgenic mice may be associated with the increased intercellular space,reduced cell junction length and decreased cell junction number,which lead to deficient or aberrant GJIC in nasopharyngeal epithelia of TgN(p53mt-LMP1)/HT transgenic mice.
PART TWO The intervening effect of Qi-boosting toxin-resolving formula on the GJIC in nasopharyngeal epithelia of TgN (p53mt-LMP1)/HT transgenic mice and its affection on the developing process of precancerous lesion in nasopharyngeal epithelia
Objective:To investigate the effect of Qi-Boosting Toxin-Resolving Formula (QBTRF) on the GJIC in nasopharyngeal epithelia of TgN (p53mt-LMP1)/HT transgenic mice and its affection on the developing process of precancerous lesion in nasopharyngeal epithelia. Methods:Seventy two transgenic mice of TgN(p53mt-LMP1)/HT were randomly divided into 3 groups, i.e. modeling group (MG), treating group (QG) with QBTRF and positive controlling group (TG) with tretinoin, with 24 animals in each. All these animals were treated by N, N'-dinitrosopiperazine (DNP), given in a dose of 1.0mg/10 g each time by subcutaneous injection, two times per week and lasted for 14 weeks, with a total injection number of 28 times and without the use of 12-O-tetradecanoylphorbol (TPA) as carcinogenic promoting agent as in routine carcinogenesis-inducing experiment. The animals in MG were treated by 0.2 ml of normal saline in the way of intragastric administration, those in QG were treated by 0.2 ml of concentrated decoction of QBTRF by lavage, and ones in TG treated by 0.062 mg of tretinoin only in the same volume of solution for each mouse, all being treated once each day. Moreover,24 wild mice in the same strain were taken as the normal controlling group (NG), without any additional intervening treatment for them, other than the use of carcinogenesis-inducing agent in the same way as above. Then, these mice were put into death to collect tissue samples from their nasopharyngeal for pathohistological observation of precancerous lesion and expressive activity determination of Cx43, Cx32, Cx26 proteins and their responsible mRNA, respectively.
Results:The nasopharyngeal epithelia of MG had the charactstics of malignant by pathohistological and the change of plasma membrane had the structure of pseudopodia. Meanwhile, the increased intercellular space, reduced cell junction length and decreased cell junction number were observed, and the shape and structrue of mitochondrial was abnormal under the electro microscopy. In contrast, those animals in QG, TG and NG had no such changes seen. The expressive levels of Cx43, Cx32, Cx26 proteins and their responsible mRNA were significantly higher in QG than those in MG, TG and NG (P＜0.05). Meanwhile, the expressive levels of proteins Cx43, Cx32, Cx26 and their transcripted mRNA were significantly declined respectively in QG, when compared with that of MG and TG (P＜0.05).
Conclusions:The intervening effect of herbal medicine QBTRF on the development of precancerous lesion in nasopharyngeal epithelia of TgN (p53mt-LMP1)/HT may be correlated with the restoration of exogenous connexin expression and GJIC, which may effectively inhibit the proliferating potentiality and actively induce apoptotic activity of nasopharyngeal epithelia. Now GJIC become a potential anti-oncogenic target for cancer prevention and treatment.
第一部分TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞间隙连接结构特征及其与鼻咽黏膜上皮细胞癌前病变的关系
目的：明确TgN(p53mt-LMP1)/HT小鼠鼻咽上皮细胞癌变与细胞间隙连接通讯的关系。方法：G10代模型鼠按12、15、18月龄随机分为3组,每组各12只。每组另设同品系健康野生小鼠为对照组,每组12只。观察不同月龄转基因小鼠鼻咽黏膜上皮细胞超微病理学特征与细胞间隙连接变化;用免疫组化、Western-blot法、RT-PCR技术检测Cx43、Cx32、Cx26及其mRNA的表达水平；并对各蛋白表达水平进行相关性分析。结果：TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞异型性改变随月龄增加而呈现加重趋势；细胞核、线粒体形态发生改变,细胞间隙增宽,细胞连接明显减少或缺失,连接长度缩短,对照组无相应改变。各月龄转基因小鼠鼻咽黏膜Cx43、Cx32、Cx26及其mRNA表达水平随月龄增长而呈现下降趋势。其中15月、18月龄转基因小鼠鼻咽上皮细胞Cx43、Cx32、Cx26蛋白表达水平明显低于12月龄转基因小鼠,差异有统计学意义(P值均小于0.05)；15月龄、18月龄小鼠鼻咽上皮细胞Cx43、Cx32、Cx26蛋白表达水平无显著性差异(P>0.05)。各月龄转基因小鼠鼻咽黏膜上皮细胞Cx43、Cx32、Cx26及其mRNA表达水平均低于同月龄野生小鼠,差异均有统计学意义(P<0.05或P<0.01)。对各月龄转基因鼠Cx43、Cx32、Cx26表达水平关联性进行分析,发现Cx43-Cx32、Cx43-Cx26、Cx32-Cx26呈正相关(P<0.05)。
结论：TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞异型性改变随时间增长而加重,细胞间隙增宽,细胞连接明显减少或缺失,连接长度缩短可能与Cx43、Cx32、Cx26及其mRNA表达水平下降,细胞间隙连接通讯功能障碍有关。
第二部分益气解毒方对TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞间隙连接通讯的干预效应及其对鼻咽黏膜上皮细胞癌前病变发展过程的影响
目的：研究益气解毒方对TgN(p53mt-LMP1)/HT小鼠鼻咽黏膜上皮细胞间隙连接通讯的干预效应及其对鼻咽上皮细胞癌变过程的影响。方法：模型鼠72只随机分为3组,模型组[(modeling group, MG),每天灌胃生理盐水0.2ml]、益气解毒方干预组[(Qi-boosting toxin-resolving intervening group, QG),每天灌胃益气解毒方剂0.2ml]、维A酸阳性对照组[(Tretinoin positive controlling group, TG),每天灌胃维A酸药剂0.2ml]；同品系健康野生鼠24只作阴性对照组(Natural group, NG),不另加其他干预因素。各组均用诱癌剂二亚硝基哌嗪(N, N'-dinitrosopiperazine, DNP)进行处理,以100mg/kg体重皮下注射,每周2次,共计28次,共处理14周,但不应用促癌剂佛波醇酯((12-O-tetradecanoylphorbol, TPA)。观察各组小鼠鼻咽黏膜组织病理学、超微病理学特征与细胞间隙连接变化；用免疫组化、Western-blot法、RT-PCR技术检测Cx43、Cx32、Cx26及其mRNA的表达水平。结果：MG组鼻咽黏膜上皮细胞异型性增生明显,有癌变特征,TG组、QG组鼻咽黏膜上皮细胞表现轻度异型增生,NG组部分鼻咽黏膜上皮细胞呈单纯性增生。MG组细胞膜呈伪足样改变,细胞核形态异常,核切迹增多,线粒体肿胀肥大或透明变性,乃至空泡状,细胞间隙增宽,细胞连接明显减少或缺失,连接长度缩短,TG组、NG组、QG组无上述改变。MG组Cx43、Cx32、Cx26及其mRNA表达水平显著低于TG组、NG组、QG组(P<0.05和P<0.01),而QG组上述蛋白及其mRNA表达量显著高于其在MG组和TG组中的表达水平(P<0.05)。结论：益气解毒方逆转鼻咽黏膜上皮细胞癌前病变的发展,可能通过恢复细胞间隙连接通讯功能,抑制细胞增殖,诱导细胞凋亡而实现。GJIC已成为肿瘤预防和治疗研究的潜在靶点之一。
This paper is composed of following two parts.
PART ONE Gap junctional intercellular characteristics in nasopharyngeal epithelia of TgN(p53mt-LMP1)/HT transgenic mice and its association with the precancerous lesion in nasopharyngeal epithelia
Objective:To investigate the characteristics of GJIC in nasopharyngeal epithelia of TgN(p53mt-LMP1)/HTcorrelation and its association with the precancerous lesion in nasopharyngeal epithelia.
Methods:Included in this part of study were 36 animals randomly chosen from the generation of G10 TgN(p53mt-LMP1)/HT transgenic mice at the month age of 12th,15th and 18th respectively with positively expressed p53 and LMP1 activities, divided into 3 groups with 12 mice in each. Another 3 groups of wild mice in the same strain were taken as the negative control group, with the same age animals in each group and at the same month age as well respectively. Then, their nasopharyngeal mucosa membrane was taken to prepare tissue samples. The morphological changes and cell gap junction of nasopharyngeal epithelia were observed under light microscope and transmission electronic microscope at the same time. The expressive activities of Cx43, Cx32, Cx26 proteins and their responsible mRNA were detected by immunohistochemistry, western blot and reverse transcription polymerase chain reaction (RT-PCR), respectively.
Results:An obviously increased tendency of precancerous lesions in the nasopharyngeal epithelia of TgN(p53mt-LMP1)/HT transgenic mice was shown with the increase of the age, and the shape of nuclear and mitochondrial was abnormal as shown by the electronic microscopy. Meanwhile, the increased intercellular space, reduced cell junction length and decreased cell junction number were observed obviously, with the increasing of the age. There was a decreasing tendency seen in the expressive activities of Cx43, Cx32, Cx26 proteins and their responsible mRNA in these tissue samples. The expression of Cx43, Cx32, Cx26 proteins in the animals at the age of 15th and 18th was significantly lower than those at the age of 12th month (P<0.05). There was no statistical significance of the expression of Cx43, Cx32, Cx26 proteins and their responsible mRNA in the transgenic mice at the age of 15th and 18th(P> 0.05). The expression level of Cx43,Cx32,Cx26 protein and mRNA were decreased significantly compared with the wild groups at the same age (P<0.05). The correlation anlysis of Cx43,Cx32,Cx26 of the groups of the transgenics mice: Cx43-Cx32, Cx43-Cx26, Cx32-Cx26 were positive correlation (P<0.05).
Conclusions:It can be concluded that the developing process of precancerous lesion in nasopharyngeal epithelia was possibly associated with the decreased expressive activity of Cx43, Cx32, Cx26 proteins and their responsible mRNA. Indeed, the carcinogenesis of nasopharyngeal epithelia of TgN (p53mt-LMP1)/ HT transgenic mice may be associated with the increased intercellular space,reduced cell junction length and decreased cell junction number,which lead to deficient or aberrant GJIC in nasopharyngeal epithelia of TgN(p53mt-LMP1)/HT transgenic mice.
PART TWO The intervening effect of Qi-boosting toxin-resolving formula on the GJIC in nasopharyngeal epithelia of TgN (p53mt-LMP1)/HT transgenic mice and its affection on the developing process of precancerous lesion in nasopharyngeal epithelia
Objective:To investigate the effect of Qi-Boosting Toxin-Resolving Formula (QBTRF) on the GJIC in nasopharyngeal epithelia of TgN (p53mt-LMP1)/HT transgenic mice and its affection on the developing process of precancerous lesion in nasopharyngeal epithelia. Methods:Seventy two transgenic mice of TgN(p53mt-LMP1)/HT were randomly divided into 3 groups, i.e. modeling group (MG), treating group (QG) with QBTRF and positive controlling group (TG) with tretinoin, with 24 animals in each. All these animals were treated by N, N'-dinitrosopiperazine (DNP), given in a dose of 1.0mg/10 g each time by subcutaneous injection, two times per week and lasted for 14 weeks, with a total injection number of 28 times and without the use of 12-O-tetradecanoylphorbol (TPA) as carcinogenic promoting agent as in routine carcinogenesis-inducing experiment. The animals in MG were treated by 0.2 ml of normal saline in the way of intragastric administration, those in QG were treated by 0.2 ml of concentrated decoction of QBTRF by lavage, and ones in TG treated by 0.062 mg of tretinoin only in the same volume of solution for each mouse, all being treated once each day. Moreover,24 wild mice in the same strain were taken as the normal controlling group (NG), without any additional intervening treatment for them, other than the use of carcinogenesis-inducing agent in the same way as above. Then, these mice were put into death to collect tissue samples from their nasopharyngeal for pathohistological observation of precancerous lesion and expressive activity determination of Cx43, Cx32, Cx26 proteins and their responsible mRNA, respectively.
Results:The nasopharyngeal epithelia of MG had the charactstics of malignant by pathohistological and the change of plasma membrane had the structure of pseudopodia. Meanwhile, the increased intercellular space, reduced cell junction length and decreased cell junction number were observed, and the shape and structrue of mitochondrial was abnormal under the electro microscopy. In contrast, those animals in QG, TG and NG had no such changes seen. The expressive levels of Cx43, Cx32, Cx26 proteins and their responsible mRNA were significantly higher in QG than those in MG, TG and NG (P＜0.05). Meanwhile, the expressive levels of proteins Cx43, Cx32, Cx26 and their transcripted mRNA were significantly declined respectively in QG, when compared with that of MG and TG (P＜0.05).
Conclusions:The intervening effect of herbal medicine QBTRF on the development of precancerous lesion in nasopharyngeal epithelia of TgN (p53mt-LMP1)/HT may be correlated with the restoration of exogenous connexin expression and GJIC, which may effectively inhibit the proliferating potentiality and actively induce apoptotic activity of nasopharyngeal epithelia. Now GJIC become a potential anti-oncogenic target for cancer prevention and treatment.
引文
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