白血病细胞凋亡相关基因的鉴定及其作用研究
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摘要
细胞凋亡与肿瘤的发生、发展密切相关,一直是肿瘤病因学及治疗学中的研究热点。激活素A (Activin A)属于转化生长因子β(TGF-β)超家族成员,是一种多功能生长和分化因子,在初期胚形成,神经、造血细胞增殖和分化等多方面扮演着重要角色,研究显示激活素A具有诱导小鼠B细胞杂交瘤凋亡作用,但有关其机制仍然不清楚。为了寻找介导激活素诱导肿瘤细胞凋亡基因,我们采用激活素A刺激小鼠B细胞杂交瘤,将其诱导的高表达基因克隆入pcDNA3真核表达载体,然后再转染入体外培养的小鼠B细胞杂交瘤,观察其诱导小鼠B细胞杂交瘤凋亡作用,并进一步采用多种肿瘤细胞验证其诱导肿瘤细胞凋亡效应。研究揭示克隆的基因具有诱导小鼠和人白血病细胞凋亡作用,因此将该基因命名为白血病细胞凋亡相关基因(Leukemia Cell Apoptosis-related Gene, LCARG),具体研究结果如下。
1.激活素A可以上调B细胞杂交瘤2B12细胞LCARG的表达,在12h达高峰。LCARG可以增强激活素A抑制2B12细胞增殖,促进其诱导2B12细胞凋亡。LCARG siRNA降低激活素A诱导2B12细胞凋亡作用。
2. LCARG单独作用也可以抑制B细胞杂交瘤2B12细胞增殖、抗体分泌,早期可以引起Annexine V膜外翻、晚期诱导Caspase3活化,细胞出现DNA断裂、核碎裂等典型的凋亡变化。
3.检测发现LCARG作用2B12细胞后线粒体凋亡途径的调控因子Bax/Bcl-2表达比例上调,细胞浆内Cytochrome-C含量增加,内质网应激途径标志性分子Caspase-12 mRNA水平升高,死亡受体途径Caspase8 mRNA表达水平及活性无改变。提示LCARG诱导肿瘤细胞凋亡主要与线粒体途径及内质网途径有关,而与死亡受体途径可能无关。
4.为了验证LCARG诱导肿瘤细胞凋亡作用,本研究观察了过表达LCARG对人Jurkat和Raji细胞,以及小鼠Yac-1、EL-4、RAW264.7、Hep1-6、Neuro-2a、CHO和L929细胞系的影响。结果显示,LCARG不同程度抑制Jurkat、Raji、Yac-1、EL-4以及RAW264.7细胞增殖；流式细胞术检测可见明显的亚二倍体凋亡峰；对Yac-1、Jurkat细胞进行形态学检测可见细胞折光度消失、体积缩小、核膜皱缩、染色质固缩边集被包裹成核小体等凋亡形态学改变；但LCARG并不能诱导Hep1-6、Neuro-2a以及L929细胞凋亡。上述结果提示该基因主要诱导白血病样肿瘤细胞凋亡。
5.进一步对Yac-1细胞的检测显示LCARG可以活化Caspase3,剪切DNA断裂形成典型的DNA-Ladder图谱；不改变Caspase8表达水平,上调Bax表达,下调Bcl-2表达水平。该结果进一步证实LCARG诱导肿瘤细胞凋亡与线粒体途径有关,而与死亡受体途径无关。
6.研究显示参与激活素Smads信号传导途径的信号促进蛋白Smad3、信号抑制蛋白Smad6单独应用均不能诱导小鼠B细胞杂交瘤2B12细胞凋亡。
结论,本研究揭示LCARG属于新的白血病样肿瘤细胞凋亡基因,主要通过线粒体途径以及内质网途径诱导肿瘤细胞凋亡；LCARG可能是介导激活素A诱导肿瘤细胞凋亡的关键性细胞内信号分子。本研究不仅发现新的诱导肿瘤细胞凋亡基因,也为开发新的抗肿瘤基因治疗药物奠定了研究基础。
Apoptosis (apoptosis), also known as programmed cell death (PCD), is the active dying process of cells, has an important role in regulating organism development, controling cell growth, maintaining a stable internal environment. Apoptosis is preferred by the medical workers for causing no inflammation and has become a cancer etiology, pathology and oncology therapeutics research focus.At present, most cancer therapy drugs play roles by inducing tumor cells apoptosis, therefore, scholars in cancer gene therapy research hope to find more effective tumor cell apoptosis gene and provide new target for cancer therapy.
Activin A belongs to transforming growth factor-β(TGF-β) superfamily member, is a multifunctional growth and differentiation factor, plays an important role in the early embryo formation, neural, hematopoietic cell proliferation and differentiation and other aspects.Previous research also showed that activin A can induce hybridoma B-cell apoptosis, but the mechanism is still unclear. In order to find a new apoptotic genes, we have adopted that activin A stimulated mouse B-cell hybridoma, genes high expression was cloned into pcDNA3 eukaryotic expression vector and was transfected into cultured mouse B-cell hybridization tumors. We found it induced apoptosis in B-cell hybridoma, further research was done to validate its effect of inducing tumor cell apoptosis using a variety of tumor cells. Our study revealed the gene induce human and mouse leukemia cell apoptosis but can not induce cells apoptosis which derive from other organizations,such as L929, Neuro-2a et al. So the gene was named as Leukemia Cell Apoptosis-related Gene, LCARG. Specific research is as follows.
Part one:Activin induced LCARG expression
By RT-PCR, LCARG expression was detected in 2B12 cells, and it was confirmed that activin A induced LCARG expression, which peaked at 12h.
Part two:The relationship of LCARG and Activin induced 2B12 apoptosis
Further detection showed that LCARG could enhance activin A to inhibit the proliferation of hybridoma cells, antibody secretion, promote Activin induce apoptosis, on the other hand.
Part three:LCARG induced 2B12 cell apoptosis Over expression and SiRNA were used to investigate LCARG induce hybridoma 2B12 apoptosis, including prolifration assay, ELISA assay detected cells antibody-secreting function, morphology observation via Gimsa or Hochest-33258 staining, electron microscope, DNA Ladder,flow cytometry detect apoptosis and cell cycle of 2B12 cell after PI and Annexine V staining, Fluorospectrophotometry detected the activation of Caspase3 in 2B12 cells.The results indicated that LCARG could inhibit the proliferation of hybridoma 2B12 cells, decrease antibody-secreting, show the typical phenomenon of apoptosis such as cells diopter disappear, smaller in size, nuclear membrane shrinkage, chromatin condensation and margination, nucleosome formation; cause early Annexine V membrane eversion, cell cycle arrest and sub-diploid peak obtained, induce Caspase3 activation, cause late DNA breakage and nuclear fragmentation. LCARG-SiRNA inhibited ActivinA induce 2B12 apoptosis.
Part four:Further investigation about the pathway of LCARG induce 2B12 apoptosis
Bax and Bcl-2 are known as the main regulation factors in mitochondrial apoptosis pathway,it is well documented that Bax translocates from cytosol to the outer membrane of mitochondria and regulates mitochondrial permeability, allowing the passage of cytochrome C through the membrane,induced cell apoptosis. Caspase-12 is known as a critical signal factor which works in ERS and Caspase8 is known as a critical signal factor which works in death receptor pathway.Weasten-blotting tests found that LCARG induce an up-regulation of Bax and caused a disruption of the mitochondrial membrane potential as well as an increase of Cytochrome-c content in the cytosol, but have no distinguished influence on Bcl-2 expression. RT-PCR revealed Caspase-12 level in 2B12cells increased after transfed with LCARG 24 houres but Caspase8 mRNA expression level had no significant changes. Above studies have shown that LARG-induced apoptosis in tumor cells mainly related to mitochondrial pathway as well as the means of the endoplasmic reticulum, but may not be related with the death receptor pathway.
Part five:The effect of LCARG on other tumor cells such as Jurkat,Yac-1 et al
In order to further verify that LCARG can induce apoptosis in tumor cells, we selected human cell lines Jurkat and Raji cell lines as well as mouse cell lines Yac-1, EL-4, RAW264.7, Hep1-6, Neuro-2a, CHO, and L929 cell lines. The proliferation results shew that LARG inhibited growth of Jurkat, Raji, Yac-1, EL-4, as well as RAW264.7 cell in different degrees; morphological detection of Jurkat and Yac-1 shew that cells diopter disappeared, smaller in size, nuclear membrane shrinkage, chromatin condensation and margination, wrapped into a nucleosome. Flow cytometry detected significant apoptotic sub-diploid peak in Jurkat, Raji, Yac-1, EL-4 and RAW264.7 cell lines, increase Bax protein expression in Yac-1 cells. Further tests on the Yac-1 and RAW 264.7 shew LCARG induce Caspase3 activation, induce DNA break and a typical DNA-Ladder map formated; but can not change the expression of Caspase8 levels. Proliferation test and Flow cytometry shew that LCARG has no effect on Neuro-2a, L929, CHO. These results suggest that the gene can specificly induce leukemia-like tumor cell apoptosis.
Part six:The effect of other signaling protein in Activin signal transduction pathway on 2B12
Smad 3 is an enhanced signaling protein and Smad 6 is an inhibited signaling protein in activin signal transduction pathway. We tested whether they could induce 2B12 apoptosis through a series of experiments, cell proliferation asaay and flow cytometry shew Smad3, and Smad6 can not induce apoptosis in 2B12 cells.
In summary,This study found a new tumor cell apoptosis gene LCARG, and determined the gene can induce leukemia tumor cell apoptosis, induced apoptosis mainly through mitochondrial pathway and endoplasmic reticulum pathway but may not be related with the death receptor pathway, revealed LCARG is the key signaling molecule that mediated activin A induced apoptosis of tumor cells, described LCARG anti tumor effect in vivo, laid a research base for the development of new tumor apoptosis induced medicine in anti-cancer gene therapy.
1.激活素A可以上调B细胞杂交瘤2B12细胞LCARG的表达,在12h达高峰。LCARG可以增强激活素A抑制2B12细胞增殖,促进其诱导2B12细胞凋亡。LCARG siRNA降低激活素A诱导2B12细胞凋亡作用。
2. LCARG单独作用也可以抑制B细胞杂交瘤2B12细胞增殖、抗体分泌,早期可以引起Annexine V膜外翻、晚期诱导Caspase3活化,细胞出现DNA断裂、核碎裂等典型的凋亡变化。
3.检测发现LCARG作用2B12细胞后线粒体凋亡途径的调控因子Bax/Bcl-2表达比例上调,细胞浆内Cytochrome-C含量增加,内质网应激途径标志性分子Caspase-12 mRNA水平升高,死亡受体途径Caspase8 mRNA表达水平及活性无改变。提示LCARG诱导肿瘤细胞凋亡主要与线粒体途径及内质网途径有关,而与死亡受体途径可能无关。
4.为了验证LCARG诱导肿瘤细胞凋亡作用,本研究观察了过表达LCARG对人Jurkat和Raji细胞,以及小鼠Yac-1、EL-4、RAW264.7、Hep1-6、Neuro-2a、CHO和L929细胞系的影响。结果显示,LCARG不同程度抑制Jurkat、Raji、Yac-1、EL-4以及RAW264.7细胞增殖；流式细胞术检测可见明显的亚二倍体凋亡峰；对Yac-1、Jurkat细胞进行形态学检测可见细胞折光度消失、体积缩小、核膜皱缩、染色质固缩边集被包裹成核小体等凋亡形态学改变；但LCARG并不能诱导Hep1-6、Neuro-2a以及L929细胞凋亡。上述结果提示该基因主要诱导白血病样肿瘤细胞凋亡。
5.进一步对Yac-1细胞的检测显示LCARG可以活化Caspase3,剪切DNA断裂形成典型的DNA-Ladder图谱；不改变Caspase8表达水平,上调Bax表达,下调Bcl-2表达水平。该结果进一步证实LCARG诱导肿瘤细胞凋亡与线粒体途径有关,而与死亡受体途径无关。
6.研究显示参与激活素Smads信号传导途径的信号促进蛋白Smad3、信号抑制蛋白Smad6单独应用均不能诱导小鼠B细胞杂交瘤2B12细胞凋亡。
结论,本研究揭示LCARG属于新的白血病样肿瘤细胞凋亡基因,主要通过线粒体途径以及内质网途径诱导肿瘤细胞凋亡；LCARG可能是介导激活素A诱导肿瘤细胞凋亡的关键性细胞内信号分子。本研究不仅发现新的诱导肿瘤细胞凋亡基因,也为开发新的抗肿瘤基因治疗药物奠定了研究基础。
Apoptosis (apoptosis), also known as programmed cell death (PCD), is the active dying process of cells, has an important role in regulating organism development, controling cell growth, maintaining a stable internal environment. Apoptosis is preferred by the medical workers for causing no inflammation and has become a cancer etiology, pathology and oncology therapeutics research focus.At present, most cancer therapy drugs play roles by inducing tumor cells apoptosis, therefore, scholars in cancer gene therapy research hope to find more effective tumor cell apoptosis gene and provide new target for cancer therapy.
Activin A belongs to transforming growth factor-β(TGF-β) superfamily member, is a multifunctional growth and differentiation factor, plays an important role in the early embryo formation, neural, hematopoietic cell proliferation and differentiation and other aspects.Previous research also showed that activin A can induce hybridoma B-cell apoptosis, but the mechanism is still unclear. In order to find a new apoptotic genes, we have adopted that activin A stimulated mouse B-cell hybridoma, genes high expression was cloned into pcDNA3 eukaryotic expression vector and was transfected into cultured mouse B-cell hybridization tumors. We found it induced apoptosis in B-cell hybridoma, further research was done to validate its effect of inducing tumor cell apoptosis using a variety of tumor cells. Our study revealed the gene induce human and mouse leukemia cell apoptosis but can not induce cells apoptosis which derive from other organizations,such as L929, Neuro-2a et al. So the gene was named as Leukemia Cell Apoptosis-related Gene, LCARG. Specific research is as follows.
Part one:Activin induced LCARG expression
By RT-PCR, LCARG expression was detected in 2B12 cells, and it was confirmed that activin A induced LCARG expression, which peaked at 12h.
Part two:The relationship of LCARG and Activin induced 2B12 apoptosis
Further detection showed that LCARG could enhance activin A to inhibit the proliferation of hybridoma cells, antibody secretion, promote Activin induce apoptosis, on the other hand.
Part three:LCARG induced 2B12 cell apoptosis Over expression and SiRNA were used to investigate LCARG induce hybridoma 2B12 apoptosis, including prolifration assay, ELISA assay detected cells antibody-secreting function, morphology observation via Gimsa or Hochest-33258 staining, electron microscope, DNA Ladder,flow cytometry detect apoptosis and cell cycle of 2B12 cell after PI and Annexine V staining, Fluorospectrophotometry detected the activation of Caspase3 in 2B12 cells.The results indicated that LCARG could inhibit the proliferation of hybridoma 2B12 cells, decrease antibody-secreting, show the typical phenomenon of apoptosis such as cells diopter disappear, smaller in size, nuclear membrane shrinkage, chromatin condensation and margination, nucleosome formation; cause early Annexine V membrane eversion, cell cycle arrest and sub-diploid peak obtained, induce Caspase3 activation, cause late DNA breakage and nuclear fragmentation. LCARG-SiRNA inhibited ActivinA induce 2B12 apoptosis.
Part four:Further investigation about the pathway of LCARG induce 2B12 apoptosis
Bax and Bcl-2 are known as the main regulation factors in mitochondrial apoptosis pathway,it is well documented that Bax translocates from cytosol to the outer membrane of mitochondria and regulates mitochondrial permeability, allowing the passage of cytochrome C through the membrane,induced cell apoptosis. Caspase-12 is known as a critical signal factor which works in ERS and Caspase8 is known as a critical signal factor which works in death receptor pathway.Weasten-blotting tests found that LCARG induce an up-regulation of Bax and caused a disruption of the mitochondrial membrane potential as well as an increase of Cytochrome-c content in the cytosol, but have no distinguished influence on Bcl-2 expression. RT-PCR revealed Caspase-12 level in 2B12cells increased after transfed with LCARG 24 houres but Caspase8 mRNA expression level had no significant changes. Above studies have shown that LARG-induced apoptosis in tumor cells mainly related to mitochondrial pathway as well as the means of the endoplasmic reticulum, but may not be related with the death receptor pathway.
Part five:The effect of LCARG on other tumor cells such as Jurkat,Yac-1 et al
In order to further verify that LCARG can induce apoptosis in tumor cells, we selected human cell lines Jurkat and Raji cell lines as well as mouse cell lines Yac-1, EL-4, RAW264.7, Hep1-6, Neuro-2a, CHO, and L929 cell lines. The proliferation results shew that LARG inhibited growth of Jurkat, Raji, Yac-1, EL-4, as well as RAW264.7 cell in different degrees; morphological detection of Jurkat and Yac-1 shew that cells diopter disappeared, smaller in size, nuclear membrane shrinkage, chromatin condensation and margination, wrapped into a nucleosome. Flow cytometry detected significant apoptotic sub-diploid peak in Jurkat, Raji, Yac-1, EL-4 and RAW264.7 cell lines, increase Bax protein expression in Yac-1 cells. Further tests on the Yac-1 and RAW 264.7 shew LCARG induce Caspase3 activation, induce DNA break and a typical DNA-Ladder map formated; but can not change the expression of Caspase8 levels. Proliferation test and Flow cytometry shew that LCARG has no effect on Neuro-2a, L929, CHO. These results suggest that the gene can specificly induce leukemia-like tumor cell apoptosis.
Part six:The effect of other signaling protein in Activin signal transduction pathway on 2B12
Smad 3 is an enhanced signaling protein and Smad 6 is an inhibited signaling protein in activin signal transduction pathway. We tested whether they could induce 2B12 apoptosis through a series of experiments, cell proliferation asaay and flow cytometry shew Smad3, and Smad6 can not induce apoptosis in 2B12 cells.
In summary,This study found a new tumor cell apoptosis gene LCARG, and determined the gene can induce leukemia tumor cell apoptosis, induced apoptosis mainly through mitochondrial pathway and endoplasmic reticulum pathway but may not be related with the death receptor pathway, revealed LCARG is the key signaling molecule that mediated activin A induced apoptosis of tumor cells, described LCARG anti tumor effect in vivo, laid a research base for the development of new tumor apoptosis induced medicine in anti-cancer gene therapy.
引文
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53.徐桂月,张鹏宇,王爽骥,台桂香,劳凤学,杨煜,崔雪玲,柳忠辉.激活素受体相互作用蛋白3的基因克隆及其免疫学特性研究[J].中国免疫学杂志,2006,22(2)：109-113,118.
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69.严馨蕊,鲍永利,董学斌等.抗重组GST单克隆抗体制备及其在融合蛋白纯化中的应用.细胞与分子免疫学杂志。2001,17(4)：365-367
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72. Tsuchida K, Nakatani M, Matsuzaki T,,et al.Novel factors in regulation of activin signaling. Mol Cell Endocrinol,2004; 225(1):1-8.
73. Tsuchida K, Matsuzaki T, Yamakawa N,,et al. Intracellular and extracellular control of activin function by novel regulatory molecules. Mol Cell Endocrinol,2001; 180(1):25-31.
74. Zhang HJ, Tai GX, Zhou J,,et al. Regulation of activin receptor-interacting protein 2 expression in mouse hepatoma Hepa1-6 cells and its relationship with collagentype IV. World J Gastroenterol 2007; 13(41):5501-5505.
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