从线粒体介导的失巢凋亡途径探讨健脾益肾冲剂防治胃癌复发转移的分子机制
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摘要
胃癌是严重威胁人民生命健康的恶性肿瘤之一,在我国胃癌的发生率在各类恶性肿瘤中居第2位,病死率居各类恶性肿瘤中第1位,在老年人群中病死率有增加的趋势。因此,寻找有效治疗胃癌的药物和方法是目前抗肿瘤研究的一个重要课题。中医药疗法是胃癌综合治疗中的重要手段之一,中药对于降低术后复发率、减轻放化疗不良反应、延长患者生存期、改善患者的生存质量有着重要的意义。健脾益肾冲剂是导师在长期防治胃癌术后复发转移的临床经验和多年的实验研究的基础上研制而成的,在实际应用中显示了良好的疗效。本课题正是在导师前期工作的基础上,以国家自然科学基金课题(NO.30600839)为依托开展的,研究工作从动物实验、细胞实验延伸至临床,采用流式细胞技术(FCM)、TUNEL、AV/PI、Realtime RT-PCR.免疫组化(IHC)等技术,从整体——细胞——分子水平,深入探讨了健脾益肾冲剂防治胃癌术后复发转移的作用机制。取得的主要研究结论和成果如下：
1.健脾益肾冲剂是导师在长期防治胃癌术后复发转移的临床经验和多年的实验研究的基础上研制而成的,经过多年的临床应用显示出良好的疗效。通过动物实验进一步证实其可以抑制实验动物复发瘤的生长,推迟肺转移的发生,还可以减少肿瘤的侵袭和转移。其中最高复发瘤抑制率为术后10天时(63.87%),最高肺转移抑制率为术后5天时(40%)
2.采用TUNEL法和AV/PI双染色两种方法,测定615小鼠复发灶、转移灶肿瘤组织细胞凋亡率,证实健脾益肾冲剂具有诱导615小鼠前胃癌肺转移灶和复发灶中肿瘤细胞凋亡的作用(转移灶和复发灶细胞凋亡指数(AI%)分别为4.88±2.56%和9.53±0.26%,明显高于模型组,P＜0.05),从而减少肿瘤的复发和转移,达到一定的治疗效果。诱导肿瘤细胞凋亡可能是其防治复发转移的重要作用机制之一。
3.应用免疫组化方法探讨线粒体介导的细胞凋亡通路相关蛋白Caspase3、Caspase9、Cytc、Smac、Omi/HtrA2和XIAP的表达在其肿瘤细胞凋亡中的变化规律,证实健脾益肾冲剂可以促进术后复发转移小鼠模型肺转移灶中促凋亡相关蛋白caspase9、caspase 3、CytC、Smac和Omi/HtrA2的表达(与模型组相比P＜0.05),而对于凋亡抑制蛋白XIAP则影响不大(与模型组相比P>0.05)。说明健脾益肾冲剂可能通过上调线粒体介导的凋亡途径中caspase9、caspase 3和CytC、Smac、Omi/HtrA2的表达,起到促肿瘤细胞凋亡作用,这可能是健脾益肾冲剂抑制肿瘤复发和转移的重要作用机制之一。这一结论也为中药复方防治肿瘤的研究提供了更多科学依据。
4.采用RT-PCR技术,测定615小鼠复发灶、转移灶肿瘤组织中caspase9、3和Cytc、Smac、Omi/HtrA2、XIAP等凋亡相关蛋白的mRNA表达,进一步证明了健脾益肾冲剂具有促进术后复发转移小鼠模型肺转移灶中促凋亡相关蛋白caspase9、caspase 3、CytC、Smac和Omi/HtrA2表达的作用(与模型组相比P<0.05),与免疫组化方法得到的结果相一致。同时健脾益肾冲剂对凋亡途径中多个蛋白的作用及其机制的研究,也为验证中药复方的多靶点效应增添了实验依据。
5.采用poly-HEMA包被的六孔板建立了人胃低分化粘液腺癌MGC803细胞系和人胃低分化腺癌BGC823细胞系的失巢模型,通过改良的转瓶琼脂培养法建立了人胃低分化粘液腺癌MGC803细胞系和人胃低分化腺癌BGC823细胞系的肿瘤多细胞球体(MTS)模型。两种模型分别较好地模拟了肿瘤细胞的失巢状态和体内生长状态。
6.采用MTT法证实了大鼠含药(健脾益肾冲剂)血清对人胃癌MGC-803细胞系及BGC-823细胞系的生长均具有抑制作用,而且与空白大鼠血清抑制率相比较具有统计学差异,排除了大鼠血清成分对药效的干扰。并通过对不同浓度的血清抑制率的观测,确定了后续实验中将要采取的含药血清浓度和化疗药物浓度。含药血清干预浓度为15%血清浓度,DDP的干预浓度为1μg／ml。(实验中采用的大鼠血清药理学方法参照《中药含药血清体外实验操作参考规程(草案)》)
7.通过AV/PI双染色法检测了大鼠含药(健脾益肾冲剂)血清对人胃癌细胞系MGC803和BGC823失巢及多细胞球体模型的促凋亡作用,证实大鼠含药(健脾益肾冲剂)血清对人胃癌MGC-803细胞系及BGC-823细胞系失巢模型及多细胞球体(MTS)模型生长均具有诱导凋亡作用(与空白大鼠血清组相比P＜0.05),凋亡率与作用时间成正比,且中药的促凋亡作用对胃癌的这两种细胞株之间不具有差异(两者相比者P＞0.05)。
8.使用FCM检测大鼠含药(健脾益肾冲剂)血清对人胃癌细胞系MGC803和BGC823多细胞球体(MTS)模型肿瘤细胞线粒体膜电位的作用,证实健脾益肾冲剂含药血清可明显降低两种模型肿瘤细胞线粒体膜电位水平,其降低程度和作用时间呈正比。说明健脾益肾冲剂可以通过降低线粒体膜电位,诱导和促进肿瘤细胞凋亡,从而抑制肿瘤细胞的生长和转移。这可能是其防治恶性肿瘤复发转移的重要作用机制之一
9.使用比色法检测大鼠含药(健脾益肾冲剂)血清对人胃癌细胞系MGC803和BGC823多细胞球体(MTS)模型caspase3、caspase9活性的影响,观察到在两种模型中均能活化和诱导caspase3、caspase9蛋白表达(其相对活性大鼠含药血清组均高于空白血清组,P<0.05)。进一步证明健脾益肾冲剂可以通过促进caspase9和caspase3的活化和表达,使其参与凋亡的启动和执行,从而启动caspase蛋白酶级联切割过程,进而启动线粒体介导的凋亡过程,抑制肿瘤细胞的生长和转移。本研究为中药防治肿瘤复发转移提供了科学依据。
10.健脾益肾冲剂可以显著提高胃癌术后患者血清抑制人胃癌细胞系MGC803和BGC823增殖的能力。服用健脾益肾冲剂后患者血清抑制肿瘤细胞增殖能力明显高于服用前(对肿瘤细胞抑制率由10%左右提高至40%-50%),与正常对照组相比较也有意义(P<0.05)。这可能是其抑制肿瘤的复发和转移的作用机制之一。研究患者病理状态下中药复方含药血清的作用,是血清药理学方法学上的有益尝试,其结果是否更加真实反映患者血清移行成分的作用,仍有待于进一步深入研究。
本研究的创新之处：
1.理论创新：本研究提出“保护失巢凋亡是防治胃癌转移的重要机制”这一工作假说,以荷瘤小鼠术后转移动物模型和人胃癌细胞系MGC803和BGC823失巢模型及多细胞球体培养模型为载体,通过线粒体介导的信号转导途径,探讨健脾益肾冲剂保护胃癌转移过程中失巢凋亡的分子机制,验证了该假说的客观性。从一个侧面揭示了中医扶正祛邪抗肿瘤复发转移理论的内涵,具有重要的理论和实践意义。
2.方法创新：本研究引入人胃癌细胞系MGC803和BGC823多细胞球体(MTS)培养模型,进行失巢凋亡及中药复方研究,经检索查新,国内外尚未见相关报道。
3.指标创新：将线粒体凋亡信号转导途径中相关调控因子Smac、Omi/HtrA2和XIAP与胃癌的复发与转移紧密联系,进行深入研究探讨,目前在胃癌防治研究领域还鲜有报道。
Discuss on the molecule-mechanism about how Jianpiyishen medicinal granule prevent and cure the recrudesces and metastasis of gastric cancer from the Anoikis'route which induced by mitochondria
Gastric cancer is one of the common malignant tumors which threaten the people's life and health. Its incidence rate situated on the second place and fatality rate situated on the first place among the malignant tumors in our country. Therefore, it is an important topic to find out medicaments and methods which can cure the Gastric cancer effectively. The TCM therapeutics is an important means of carcinoma's integrative treatment. The Jianpiyishen medicinal granule is developed by my hierophant that based on her clinic experiences and experimental research of many years. It works favorable in practice. This research began with animal experiments; extend to cell experiments and clinic experiments. We adopted the FCM、TUNEL、AV/PI、RT-PCR、IHC......and so on, to probe into the mechanism of how Jianpiyishen medicinal granule prevent and cure the recrudesces and metastasis of gastric cancer after the surgery.
The primary disquisition conclusions and harvests are the follows:
1. The Jianpiyishen medicinal granule can restrain recrudesce tumors'development, postpone the metastasis in lungs.
2. The Jianpiyishen medicinal granule can induce tumors'cell to apoptosis which lies in the metastasis of lungs and recrudesce focuses. It might be the one important effect among the mechanisms which can prevention and cure the tumors'recrudesce and metastasis.
3. The Jianpiyishen medicinal granule can promote many proteins' expression, and those proteins link to the approach which induced by mitochondria and can cause cell's apoptosis, such like caspase9、caspase 3、CytC、Smac and Omi/HtrA2.
4. The Jianpiyishen medicinal granule can promote the mRNA of apoptosis-lined proteins such like caspase9、caspase 3、CytC、Smac and Omi/HtrA2's expression. It proved that the TCM also have multi-target effects.
5. We established the anoikis cell model of poor differentiation mucinous adenocarcinoma MGC-803 from human and poor differentiation adenocarcinoma BGC-823 from human by six-hole board covered with poly-HEMA. Then we established the MTS cell model of poor differentiation mucinous adenocarcinoma MGC-803 from human and poor differentiation adenocarcinoma BGC-823 from human by improved spinner bottle and agar culture method. The former simulate tumor cell's Anoikis-condition, and the latter simulate tumor cell's internal-condition.
6. The rat blood serum of Jianpiyishen medicinal granule can restrain the growth of MGC-803 and BGC-823 tumor cells. There are distinct differences between the rat blood serum of Jianpiyishen medicinal granule and the normal rat blood serum.
7. The rat blood serum of Jianpiyishen medicinal granule can induce the apoptosis of MGC-803 MTS and BGC-823 MTS's tumor cells, and the rate of apoptosis in direct proportion to the time.
8. The rat blood serum of Jianpiyishen medicinal granule can distinctness depresses the level of mitochondria membrane potential, and interrelates with time.
9. The rat blood serum of Jianpiyishen medicinal granule can induce the expressions of caspase9 and caspase3 in the cells of MGC-803 MTS and BGC-823 tumor cells MTS. which may induce the tumor cells to apoptosis.
10. The Jianpiyishen medicinal granule can enhance the ability of patients'blood serum to restrain the tumor cells'multiplication.
The innovation of this article:
1. We brought forward the assumption that protect the Anoikis is an important mechanism to prevention and cure gastric cancer, and proved it. It is an innovation of train of thought.
2. We first used the MTS cell model of MGC803 and BGC823 tumor cells to study the the anoikis and compound of the TCM. There are no reports about the methods we used at home and abroad. It is an innovation of method.
3. Smac、Omi/HtrA2 and XIAP which we studied are proteins being investigate among the domain of apoptosis induced by mitochondria actively, but are rarely studied in the field of gastric cancer's research. It is an innovation of index.
1.健脾益肾冲剂是导师在长期防治胃癌术后复发转移的临床经验和多年的实验研究的基础上研制而成的,经过多年的临床应用显示出良好的疗效。通过动物实验进一步证实其可以抑制实验动物复发瘤的生长,推迟肺转移的发生,还可以减少肿瘤的侵袭和转移。其中最高复发瘤抑制率为术后10天时(63.87%),最高肺转移抑制率为术后5天时(40%)
2.采用TUNEL法和AV/PI双染色两种方法,测定615小鼠复发灶、转移灶肿瘤组织细胞凋亡率,证实健脾益肾冲剂具有诱导615小鼠前胃癌肺转移灶和复发灶中肿瘤细胞凋亡的作用(转移灶和复发灶细胞凋亡指数(AI%)分别为4.88±2.56%和9.53±0.26%,明显高于模型组,P＜0.05),从而减少肿瘤的复发和转移,达到一定的治疗效果。诱导肿瘤细胞凋亡可能是其防治复发转移的重要作用机制之一。
3.应用免疫组化方法探讨线粒体介导的细胞凋亡通路相关蛋白Caspase3、Caspase9、Cytc、Smac、Omi/HtrA2和XIAP的表达在其肿瘤细胞凋亡中的变化规律,证实健脾益肾冲剂可以促进术后复发转移小鼠模型肺转移灶中促凋亡相关蛋白caspase9、caspase 3、CytC、Smac和Omi/HtrA2的表达(与模型组相比P＜0.05),而对于凋亡抑制蛋白XIAP则影响不大(与模型组相比P>0.05)。说明健脾益肾冲剂可能通过上调线粒体介导的凋亡途径中caspase9、caspase 3和CytC、Smac、Omi/HtrA2的表达,起到促肿瘤细胞凋亡作用,这可能是健脾益肾冲剂抑制肿瘤复发和转移的重要作用机制之一。这一结论也为中药复方防治肿瘤的研究提供了更多科学依据。
4.采用RT-PCR技术,测定615小鼠复发灶、转移灶肿瘤组织中caspase9、3和Cytc、Smac、Omi/HtrA2、XIAP等凋亡相关蛋白的mRNA表达,进一步证明了健脾益肾冲剂具有促进术后复发转移小鼠模型肺转移灶中促凋亡相关蛋白caspase9、caspase 3、CytC、Smac和Omi/HtrA2表达的作用(与模型组相比P<0.05),与免疫组化方法得到的结果相一致。同时健脾益肾冲剂对凋亡途径中多个蛋白的作用及其机制的研究,也为验证中药复方的多靶点效应增添了实验依据。
5.采用poly-HEMA包被的六孔板建立了人胃低分化粘液腺癌MGC803细胞系和人胃低分化腺癌BGC823细胞系的失巢模型,通过改良的转瓶琼脂培养法建立了人胃低分化粘液腺癌MGC803细胞系和人胃低分化腺癌BGC823细胞系的肿瘤多细胞球体(MTS)模型。两种模型分别较好地模拟了肿瘤细胞的失巢状态和体内生长状态。
6.采用MTT法证实了大鼠含药(健脾益肾冲剂)血清对人胃癌MGC-803细胞系及BGC-823细胞系的生长均具有抑制作用,而且与空白大鼠血清抑制率相比较具有统计学差异,排除了大鼠血清成分对药效的干扰。并通过对不同浓度的血清抑制率的观测,确定了后续实验中将要采取的含药血清浓度和化疗药物浓度。含药血清干预浓度为15%血清浓度,DDP的干预浓度为1μg／ml。(实验中采用的大鼠血清药理学方法参照《中药含药血清体外实验操作参考规程(草案)》)
7.通过AV/PI双染色法检测了大鼠含药(健脾益肾冲剂)血清对人胃癌细胞系MGC803和BGC823失巢及多细胞球体模型的促凋亡作用,证实大鼠含药(健脾益肾冲剂)血清对人胃癌MGC-803细胞系及BGC-823细胞系失巢模型及多细胞球体(MTS)模型生长均具有诱导凋亡作用(与空白大鼠血清组相比P＜0.05),凋亡率与作用时间成正比,且中药的促凋亡作用对胃癌的这两种细胞株之间不具有差异(两者相比者P＞0.05)。
8.使用FCM检测大鼠含药(健脾益肾冲剂)血清对人胃癌细胞系MGC803和BGC823多细胞球体(MTS)模型肿瘤细胞线粒体膜电位的作用,证实健脾益肾冲剂含药血清可明显降低两种模型肿瘤细胞线粒体膜电位水平,其降低程度和作用时间呈正比。说明健脾益肾冲剂可以通过降低线粒体膜电位,诱导和促进肿瘤细胞凋亡,从而抑制肿瘤细胞的生长和转移。这可能是其防治恶性肿瘤复发转移的重要作用机制之一
9.使用比色法检测大鼠含药(健脾益肾冲剂)血清对人胃癌细胞系MGC803和BGC823多细胞球体(MTS)模型caspase3、caspase9活性的影响,观察到在两种模型中均能活化和诱导caspase3、caspase9蛋白表达(其相对活性大鼠含药血清组均高于空白血清组,P<0.05)。进一步证明健脾益肾冲剂可以通过促进caspase9和caspase3的活化和表达,使其参与凋亡的启动和执行,从而启动caspase蛋白酶级联切割过程,进而启动线粒体介导的凋亡过程,抑制肿瘤细胞的生长和转移。本研究为中药防治肿瘤复发转移提供了科学依据。
10.健脾益肾冲剂可以显著提高胃癌术后患者血清抑制人胃癌细胞系MGC803和BGC823增殖的能力。服用健脾益肾冲剂后患者血清抑制肿瘤细胞增殖能力明显高于服用前(对肿瘤细胞抑制率由10%左右提高至40%-50%),与正常对照组相比较也有意义(P<0.05)。这可能是其抑制肿瘤的复发和转移的作用机制之一。研究患者病理状态下中药复方含药血清的作用,是血清药理学方法学上的有益尝试,其结果是否更加真实反映患者血清移行成分的作用,仍有待于进一步深入研究。
本研究的创新之处：
1.理论创新：本研究提出“保护失巢凋亡是防治胃癌转移的重要机制”这一工作假说,以荷瘤小鼠术后转移动物模型和人胃癌细胞系MGC803和BGC823失巢模型及多细胞球体培养模型为载体,通过线粒体介导的信号转导途径,探讨健脾益肾冲剂保护胃癌转移过程中失巢凋亡的分子机制,验证了该假说的客观性。从一个侧面揭示了中医扶正祛邪抗肿瘤复发转移理论的内涵,具有重要的理论和实践意义。
2.方法创新：本研究引入人胃癌细胞系MGC803和BGC823多细胞球体(MTS)培养模型,进行失巢凋亡及中药复方研究,经检索查新,国内外尚未见相关报道。
3.指标创新：将线粒体凋亡信号转导途径中相关调控因子Smac、Omi/HtrA2和XIAP与胃癌的复发与转移紧密联系,进行深入研究探讨,目前在胃癌防治研究领域还鲜有报道。
Discuss on the molecule-mechanism about how Jianpiyishen medicinal granule prevent and cure the recrudesces and metastasis of gastric cancer from the Anoikis'route which induced by mitochondria
Gastric cancer is one of the common malignant tumors which threaten the people's life and health. Its incidence rate situated on the second place and fatality rate situated on the first place among the malignant tumors in our country. Therefore, it is an important topic to find out medicaments and methods which can cure the Gastric cancer effectively. The TCM therapeutics is an important means of carcinoma's integrative treatment. The Jianpiyishen medicinal granule is developed by my hierophant that based on her clinic experiences and experimental research of many years. It works favorable in practice. This research began with animal experiments; extend to cell experiments and clinic experiments. We adopted the FCM、TUNEL、AV/PI、RT-PCR、IHC......and so on, to probe into the mechanism of how Jianpiyishen medicinal granule prevent and cure the recrudesces and metastasis of gastric cancer after the surgery.
The primary disquisition conclusions and harvests are the follows:
1. The Jianpiyishen medicinal granule can restrain recrudesce tumors'development, postpone the metastasis in lungs.
2. The Jianpiyishen medicinal granule can induce tumors'cell to apoptosis which lies in the metastasis of lungs and recrudesce focuses. It might be the one important effect among the mechanisms which can prevention and cure the tumors'recrudesce and metastasis.
3. The Jianpiyishen medicinal granule can promote many proteins' expression, and those proteins link to the approach which induced by mitochondria and can cause cell's apoptosis, such like caspase9、caspase 3、CytC、Smac and Omi/HtrA2.
4. The Jianpiyishen medicinal granule can promote the mRNA of apoptosis-lined proteins such like caspase9、caspase 3、CytC、Smac and Omi/HtrA2's expression. It proved that the TCM also have multi-target effects.
5. We established the anoikis cell model of poor differentiation mucinous adenocarcinoma MGC-803 from human and poor differentiation adenocarcinoma BGC-823 from human by six-hole board covered with poly-HEMA. Then we established the MTS cell model of poor differentiation mucinous adenocarcinoma MGC-803 from human and poor differentiation adenocarcinoma BGC-823 from human by improved spinner bottle and agar culture method. The former simulate tumor cell's Anoikis-condition, and the latter simulate tumor cell's internal-condition.
6. The rat blood serum of Jianpiyishen medicinal granule can restrain the growth of MGC-803 and BGC-823 tumor cells. There are distinct differences between the rat blood serum of Jianpiyishen medicinal granule and the normal rat blood serum.
7. The rat blood serum of Jianpiyishen medicinal granule can induce the apoptosis of MGC-803 MTS and BGC-823 MTS's tumor cells, and the rate of apoptosis in direct proportion to the time.
8. The rat blood serum of Jianpiyishen medicinal granule can distinctness depresses the level of mitochondria membrane potential, and interrelates with time.
9. The rat blood serum of Jianpiyishen medicinal granule can induce the expressions of caspase9 and caspase3 in the cells of MGC-803 MTS and BGC-823 tumor cells MTS. which may induce the tumor cells to apoptosis.
10. The Jianpiyishen medicinal granule can enhance the ability of patients'blood serum to restrain the tumor cells'multiplication.
The innovation of this article:
1. We brought forward the assumption that protect the Anoikis is an important mechanism to prevention and cure gastric cancer, and proved it. It is an innovation of train of thought.
2. We first used the MTS cell model of MGC803 and BGC823 tumor cells to study the the anoikis and compound of the TCM. There are no reports about the methods we used at home and abroad. It is an innovation of method.
3. Smac、Omi/HtrA2 and XIAP which we studied are proteins being investigate among the domain of apoptosis induced by mitochondria actively, but are rarely studied in the field of gastric cancer's research. It is an innovation of index.
引文
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