原发性肝癌证型分布演变规律及柴胡皂甙D诱导肝癌细胞分化的研究
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摘要
目的：
初步研究了原发性肝癌中医证型分布规律,并观察了柴胡皂甙D (SSD)对人肝癌细胞株SMMC-7721的分化诱导作用以及部分作用机制。
方法：
本文以临床观察研究的形式,通过临床流行病学的研究手段,利用横断面、病例对照以及SDS流调表的方法初步探讨了原发性肝癌中医证型分布规律及与情绪障碍的关系；实验部分则是分别通过形态学观察、生化功能和细胞周期检测、以及P38MAPK、P21~(WAF1)及NF-kB等信号转导分子表达测定来探讨SSD对肝癌细胞株SMMC-7721的诱导分化作用及相关机制。
结果：
1.原发性肝癌主要发生于40-60与60-80年龄组(P＜0.005),以男性为主(P＜0.005)。从原发性肝癌分期构成情况来看,本次收集的原发性肝癌病例主要集中在Ⅲ期；各单位原发性肝癌分期构成相比A院Ⅱ期病例比例较B、C院高x~2=8.458.P=0.004 (<0.05)。
2.从原发性肝癌证型构成情况来看,总体来说气滞血瘀型、湿热蕴结型两型较多；而从各医院证型构成来看,存在有明显的地域差异,C院(北方地区)气滞血瘀型明显高于其它两院,而A、B两院则表现为以湿热蕴结型和湿瘀搏结型.为主P=0.000(<0.017)。
3.从原发性肝癌证型与分期分布关系结果来看,总体Ⅱ、Ⅲ期证型分布明显不同(p<0.05)。肝癌临床Ⅱ期主要表现为脾虚肝郁型或气滞血瘀型,而Ⅲ期则主要表现湿热蕴结和湿瘀搏结型。
4.证型多元分析结果表明,气滞血瘀型与谷丙转氨酶、有无腹水、有无黄染关系密切(P<0.05)；湿热蕴结型与有无黄染关系密切(P<0.05)：湿瘀搏结型与有无腹水、有无黄染与该型关系密切(P<0.05)。
5.从原发性肝癌与情绪障碍关系结果来看,虽然病例组与对照组在抑郁状态的发生率方面无明显差异。但从定量的角度来讲,对于抑郁状态的评分,病例组得分较高(p＜0.05)。
6.MTT及形态学结果显示,SSD对肝癌细胞抑制作用呈一定的量效关系,20mg/L时抑制率达84%左右：SSD2.5 mg/L、5 mg/L和ATRA处理组与对照组相比平均核面积缩小(p<0.05)。
7.SSD能显著升高肝癌细胞ALB分泌量及上调ALP活性(p<0.05)：显著下调肝癌细胞内LDH活性(p<0.05)：对肝癌细胞ALT活性无明显作用(p＞0.05),但对AST活性皆有升高作用(p＜0.05)；能明显下调AFP分泌量(p<0.05),但在10mg/L时却无明显作用(p>0.05)。
8.SSD对肝癌细胞周期的影响：与对照组相比,SSD各处理组以及ATRA组皆有统计学意义(p<0.005)；其主要构成差异在G0/G1期(p＜0.005),但各处理组间无统计学意义(p>0.005)。
9.SSD对肝癌细胞P38MAP kinase、P21~(WAF1)和NF-kB表达的影响：各处理组与对照组相比皆有统计学意义(P<0.05),其中以SSD(5 mg/L、10 mg/L)剂量组最好,但它们之间相比无统计学意义。
结论：
肝癌Ⅱ期主要表现为脾虚肝郁型或气滞血瘀型,而Ⅲ期则主要表现湿热蕴结和湿热蕴结型,且肝癌患者抑郁状态程度较高；SSD对SMMC-7721细胞具有显著诱导分化作用,能够明显降低AFP的分泌量及减弱LDH活性,明显升高ALP的生物活性及增加ALB分泌量；并且将SMMC-7721的细胞周期明显阻滞于G0/G1期,从而使细胞增殖活性降低,进而趋于分化或凋亡；其作用机制可能与上调P38MAPK及p21WAF1蛋白表达,下调NF-kB表达有关。
Objective:To explore the regulation of the syndrome differentiation of Chinese medicine in primary hepatic carcinoma.To observe if Saikosapollin-d could induce differentiation, and discuss the mechanism of action initially.
Methods:To explore the regulation of the syndrome differentiation of Chinese medicine in primary hepatic carcinoma by cross-sectional study and case control study. And to study the incidence of emotional disorder in patients with PHC by the method of SDS. In the part of experiment, To study the effects of SSD on inducing differentiation and mechanisms by observing SMMC-7721 cell morphous,, detecting biochemistry function、cell cycle and expression of signal transduction molecule such as P38MAPK、P21~WAF1) and NF-KB.
Results:
1. PHC happened in 40-80 years(P<0.005) and male mainly(P<0.05). And the cases of III stage were dominantposition; To compare with B and C hospitals, the rate of II stage in A hospital was remarkable improve,x~2=8.458, P=0.004(<0.05).
2. As to construction of patterns of syndrome in PHC, the patterns of QI ZHI XUE YU and SHI RE YUN JIE were dominant totally; But the difference of region was found in construction of patterns of syndrome; To compare with B and C hospitals,the rate of QI ZHI XUE YU syndrome was higher remarkably in C hospital(the region of north);But the rates of SHI RE YUN JIE syndrome and SHI YU BO JIE syndrome were dominant,P=0.000(<0.017).
3.The construction of type syndrome of Chinese medicine were not different obviously betweenⅡandⅢstage of PHC (p<0.05). The PI XU GAN YU syndrome and QI ZHI XUE YU syndrome were dominant inⅡstage of PHC, and the SHI RE YUN JIE syndrome and SHI YU BO JIE syndrome were dominant inⅢstage of PHC.
4. The results of logistic regression:ALT、ascitic fluid and stained yellow were dominant factors in the patterns of QI ZHI XUE YU (p<0.05); Stained yellow was dominant factors in the patterns of SHI RE YUN JIE (p<0.05); Ascitic fluid and stained yellow were dominant factors in the patterns of SHI YU BO JIE (p<0.05).
5.The rate of depressions were not different(p>0.05) between control and PHC groups,but the score of PHC group was higher than control group (p<0.05).
6. Experimental result of MTT and Wright-Giemsa:SSD showed a dose-effect relationship on the inhibitory action.And the inhibition ratio was 84%in 20mg/L. The average area of cell nucleus diminished at the SSD concentration of 2.5 mg/L and 5 mg/L as well as the ATRA (p<0.05,vs control).
7.SSD could improve the secretion of ALB,up-regulate the activity of ALP and down regulate the activity of LDH in HCC significantly (p<0.05). SSD had no remarkable effect on ALT (p>0.05), but could improve the activity of AST(p<0.05). SSD could obviously down regulate the secretion of AFP (p<0.05), but had no significant effect at 10mg/L (p>0.05).
8.Effects of SSD on the cell cycle:The results showed significant difference in each group (p<0.005).The main difference was in G0/G1 (p<0.005).But it didn't show obvious difference..
9.Effects of SSD on the P38MAP kinase、NF-kB and P21~(WAF1):The effects had remarkable difference in every test groups compared with the control(P<0.05). The effects reached the peak in SSD at 5mg/L and 10 mg/L,but there was no significant difference between them.
Conclusions:In the clinicalⅡstage of HCC,the syndromes of PI XU GAN YU and QI ZHI XUE YU were dominant; In the clinicalⅢstage of HCC,the syndromes of SHI RE YUN JIE and GAN SHEN YIN XU were dominant. And the incidence rate of depression is remarkable improve in HCC. SSD had notable induce differentiation on SMMC-7721 cell, could obviously down regulate the secretion of AFP and the activity of LDH,as well as up-regulate the activity of ALP and improve the secretion of ALB. SSD could obviously hold-up the cell cycle in G_0/G_1 and depress the cell multiplication activity.So the cells had the tendency of differentiation and apoptosis.The possible mechanisms may be up-regulating P38MAPK and P21~(WAF1) and down regulating NF-kB.
初步研究了原发性肝癌中医证型分布规律,并观察了柴胡皂甙D (SSD)对人肝癌细胞株SMMC-7721的分化诱导作用以及部分作用机制。
方法：
本文以临床观察研究的形式,通过临床流行病学的研究手段,利用横断面、病例对照以及SDS流调表的方法初步探讨了原发性肝癌中医证型分布规律及与情绪障碍的关系；实验部分则是分别通过形态学观察、生化功能和细胞周期检测、以及P38MAPK、P21~(WAF1)及NF-kB等信号转导分子表达测定来探讨SSD对肝癌细胞株SMMC-7721的诱导分化作用及相关机制。
结果：
1.原发性肝癌主要发生于40-60与60-80年龄组(P＜0.005),以男性为主(P＜0.005)。从原发性肝癌分期构成情况来看,本次收集的原发性肝癌病例主要集中在Ⅲ期；各单位原发性肝癌分期构成相比A院Ⅱ期病例比例较B、C院高x~2=8.458.P=0.004 (<0.05)。
2.从原发性肝癌证型构成情况来看,总体来说气滞血瘀型、湿热蕴结型两型较多；而从各医院证型构成来看,存在有明显的地域差异,C院(北方地区)气滞血瘀型明显高于其它两院,而A、B两院则表现为以湿热蕴结型和湿瘀搏结型.为主P=0.000(<0.017)。
3.从原发性肝癌证型与分期分布关系结果来看,总体Ⅱ、Ⅲ期证型分布明显不同(p<0.05)。肝癌临床Ⅱ期主要表现为脾虚肝郁型或气滞血瘀型,而Ⅲ期则主要表现湿热蕴结和湿瘀搏结型。
4.证型多元分析结果表明,气滞血瘀型与谷丙转氨酶、有无腹水、有无黄染关系密切(P<0.05)；湿热蕴结型与有无黄染关系密切(P<0.05)：湿瘀搏结型与有无腹水、有无黄染与该型关系密切(P<0.05)。
5.从原发性肝癌与情绪障碍关系结果来看,虽然病例组与对照组在抑郁状态的发生率方面无明显差异。但从定量的角度来讲,对于抑郁状态的评分,病例组得分较高(p＜0.05)。
6.MTT及形态学结果显示,SSD对肝癌细胞抑制作用呈一定的量效关系,20mg/L时抑制率达84%左右：SSD2.5 mg/L、5 mg/L和ATRA处理组与对照组相比平均核面积缩小(p<0.05)。
7.SSD能显著升高肝癌细胞ALB分泌量及上调ALP活性(p<0.05)：显著下调肝癌细胞内LDH活性(p<0.05)：对肝癌细胞ALT活性无明显作用(p＞0.05),但对AST活性皆有升高作用(p＜0.05)；能明显下调AFP分泌量(p<0.05),但在10mg/L时却无明显作用(p>0.05)。
8.SSD对肝癌细胞周期的影响：与对照组相比,SSD各处理组以及ATRA组皆有统计学意义(p<0.005)；其主要构成差异在G0/G1期(p＜0.005),但各处理组间无统计学意义(p>0.005)。
9.SSD对肝癌细胞P38MAP kinase、P21~(WAF1)和NF-kB表达的影响：各处理组与对照组相比皆有统计学意义(P<0.05),其中以SSD(5 mg/L、10 mg/L)剂量组最好,但它们之间相比无统计学意义。
结论：
肝癌Ⅱ期主要表现为脾虚肝郁型或气滞血瘀型,而Ⅲ期则主要表现湿热蕴结和湿热蕴结型,且肝癌患者抑郁状态程度较高；SSD对SMMC-7721细胞具有显著诱导分化作用,能够明显降低AFP的分泌量及减弱LDH活性,明显升高ALP的生物活性及增加ALB分泌量；并且将SMMC-7721的细胞周期明显阻滞于G0/G1期,从而使细胞增殖活性降低,进而趋于分化或凋亡；其作用机制可能与上调P38MAPK及p21WAF1蛋白表达,下调NF-kB表达有关。
Objective:To explore the regulation of the syndrome differentiation of Chinese medicine in primary hepatic carcinoma.To observe if Saikosapollin-d could induce differentiation, and discuss the mechanism of action initially.
Methods:To explore the regulation of the syndrome differentiation of Chinese medicine in primary hepatic carcinoma by cross-sectional study and case control study. And to study the incidence of emotional disorder in patients with PHC by the method of SDS. In the part of experiment, To study the effects of SSD on inducing differentiation and mechanisms by observing SMMC-7721 cell morphous,, detecting biochemistry function、cell cycle and expression of signal transduction molecule such as P38MAPK、P21~WAF1) and NF-KB.
Results:
1. PHC happened in 40-80 years(P<0.005) and male mainly(P<0.05). And the cases of III stage were dominantposition; To compare with B and C hospitals, the rate of II stage in A hospital was remarkable improve,x~2=8.458, P=0.004(<0.05).
2. As to construction of patterns of syndrome in PHC, the patterns of QI ZHI XUE YU and SHI RE YUN JIE were dominant totally; But the difference of region was found in construction of patterns of syndrome; To compare with B and C hospitals,the rate of QI ZHI XUE YU syndrome was higher remarkably in C hospital(the region of north);But the rates of SHI RE YUN JIE syndrome and SHI YU BO JIE syndrome were dominant,P=0.000(<0.017).
3.The construction of type syndrome of Chinese medicine were not different obviously betweenⅡandⅢstage of PHC (p<0.05). The PI XU GAN YU syndrome and QI ZHI XUE YU syndrome were dominant inⅡstage of PHC, and the SHI RE YUN JIE syndrome and SHI YU BO JIE syndrome were dominant inⅢstage of PHC.
4. The results of logistic regression:ALT、ascitic fluid and stained yellow were dominant factors in the patterns of QI ZHI XUE YU (p<0.05); Stained yellow was dominant factors in the patterns of SHI RE YUN JIE (p<0.05); Ascitic fluid and stained yellow were dominant factors in the patterns of SHI YU BO JIE (p<0.05).
5.The rate of depressions were not different(p>0.05) between control and PHC groups,but the score of PHC group was higher than control group (p<0.05).
6. Experimental result of MTT and Wright-Giemsa:SSD showed a dose-effect relationship on the inhibitory action.And the inhibition ratio was 84%in 20mg/L. The average area of cell nucleus diminished at the SSD concentration of 2.5 mg/L and 5 mg/L as well as the ATRA (p<0.05,vs control).
7.SSD could improve the secretion of ALB,up-regulate the activity of ALP and down regulate the activity of LDH in HCC significantly (p<0.05). SSD had no remarkable effect on ALT (p>0.05), but could improve the activity of AST(p<0.05). SSD could obviously down regulate the secretion of AFP (p<0.05), but had no significant effect at 10mg/L (p>0.05).
8.Effects of SSD on the cell cycle:The results showed significant difference in each group (p<0.005).The main difference was in G0/G1 (p<0.005).But it didn't show obvious difference..
9.Effects of SSD on the P38MAP kinase、NF-kB and P21~(WAF1):The effects had remarkable difference in every test groups compared with the control(P<0.05). The effects reached the peak in SSD at 5mg/L and 10 mg/L,but there was no significant difference between them.
Conclusions:In the clinicalⅡstage of HCC,the syndromes of PI XU GAN YU and QI ZHI XUE YU were dominant; In the clinicalⅢstage of HCC,the syndromes of SHI RE YUN JIE and GAN SHEN YIN XU were dominant. And the incidence rate of depression is remarkable improve in HCC. SSD had notable induce differentiation on SMMC-7721 cell, could obviously down regulate the secretion of AFP and the activity of LDH,as well as up-regulate the activity of ALP and improve the secretion of ALB. SSD could obviously hold-up the cell cycle in G_0/G_1 and depress the cell multiplication activity.So the cells had the tendency of differentiation and apoptosis.The possible mechanisms may be up-regulating P38MAPK and P21~(WAF1) and down regulating NF-kB.
引文
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