NAIF1基因在胃癌细胞中的功能与机理研究
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摘要
胃癌是常见的人消化道癌症,发病率在全部人类癌症中占据第四位,同时,胃癌的致死率达到70%,远远高于其他常见的人类癌症。胃癌的高发病率与高致死率严重影响了人类健康和生活。肿瘤的侵袭转移是影响患者预后和导致高致死率的主要原因,对胃癌细胞内侵袭转移相关分子和通路的研究有利于我们更清楚地理解其分子机制,也为胃癌的早期诊断和针对性治疗提供新的分子标志物和靶点。
NAIF1是一个核凋亡诱导因子,前期研究发现NAIF1能够诱导HeLa细胞和MKN45细胞凋亡,凋亡通过线粒体途径发生,涉及到了Caspase9和Caspase3的活化,并且NAIF1在人胃癌组织和癌旁组织中呈现差异表达,癌旁组织高表达,胃癌组织低表达或不表达。但对NAIF1在细胞中的功能研究仅限于此,NAIF1在细胞内还参与了哪些通路、还发挥了哪些作用尚不清楚。
本研究以NAIF1基因和胃癌细胞系为研究对象,采用了激光共聚焦、流式细胞术、transwell、real-time Q PCR、双向电泳、免疫杂交等多种实验技术,对NAIF1基因在胃癌细胞中的表达、分布、功能、功能相关机理和对蛋白表达谱的影响等进行了研究。
我们检测到,在三株胃癌细胞系AGS、MKN45、SGC7901和一株永生化胃粘膜细胞系GES-1中,NAIF1在蛋白水平和RNA水平上均无表达。外源的NAIF1在AGS和MKN45这两株细胞中均只在细胞核内分布。过表达NAIF1能够诱导MKN45细胞产生G0/G1期的周期阻滞,并且抑制了AGS和MKN45细胞的运动能力,细胞迁移率分别下降了3倍和2.8倍。在机制研究中,我们发现NAIF1通过降低CyclinD1的表达诱导了细胞周期阻滞。在无刺激和采用血清/紫外刺激的不同情况下,NAIF1均能够降低AGS和MKN45细胞内Erk1/2>JNK的磷酸化水平,但对p38通路无影响。并且,NAIF1还降低了MKN45细胞内JNK的本底表达水平cMAPK的下游基因中,MMP2、 MMP9的表达降低。我们还发现NAIF1过表达的细胞中FAK-Ser910的磷酸化水平降低。我们推测,NAIF1可能是通过对MAPK通路的调节,来影响其下游Cyclin1、 MMP2、MMP9以及FAK的表达量或活性,进而对细胞周期和细胞的运动能力进行调控。利用蛋白质组学的方法,我们通过双向电泳实验检测到NAIF1基因在MKN45细胞内过表达后上调了5种蛋白PSMC2、PSMD13、TXNRD1、TCP1-gamma和NDUSF1的表达水平,下调了3种蛋白14-3-3epsilon RNH1和APIAOBP的表达水平。Westernblotting实验验证了TXNRD1、TCP1-gamma两种蛋白在NAIF1过表达的MKN45细胞中表达上调,14-3-3epsilon表达下调。利用基因组学的方法,我们还发现当在细胞内过表达NAIF1基因时,155个胞内基因出现了大于2倍的表达量变化,GO分析显示大部分基因参与了免疫反应调节的生物学进程。这一结果为NAIF1基因的研究提供了新的思路和方向。
本研究是首次发现NAIF1通过调节CyclinD1的表达导致了MKN45细胞出现周期阻滞,并首次发现NAIF1通过对MAPK通路及其下游基因的调控来影响细胞的运动能力。也是首次通过蛋白质组学的方法对NAIF1基因所引起的细胞蛋白谱的表达变化做出了研究。本文的研究结果具有创新意义,揭示了NAIF1基因在细胞内涉及的新的功能和新的分子机制,对于今后理解并研究NAIF1基因的功能和作用机制具有指导意义,同时对于胃癌浸润转移的治疗也提供了新的分子靶点。
As a common digestive tract cancer, the incidence of gastric cancer occupied the fourth place of all human cancers with a lethality rate of70%, which is much higher than other common human cancers. High morbidity and high mortality rate of gastric cancer has a serious impact on human health. Tumor invasion and metastasis are the main reasons for the bad prognosis of patients and lead to high lethality rate, therefore, researching the related molecules and pathways of invasion and metastasis in gastric cancer cell will not only help us with a better understanding of the molecular mechanisms, but also provide new markers and targets for gastric cancer diagnosis and therapy.
NAIF1is a nuclear apoptosis-inducing factor. Previous findings showed that NAIF1was able to induce apoptosis in HeLa cells and MKN45cells through mitochondrial pathway, and these events involved the activation of Caspase9and Caspase3, in addition, NAIF1showed a different expression between human gastric cancer tissues and adjacent tissues. However, whether NAIF1was involved in other cell functions and pathways was still unknown.
In this study, we focus on the functions and mechanisms of NAIF1in gastric cancer cells. A variety of experimental techniques were employed including confocal scanning, flow cytometry, transwell, real-time Q PCR, two-dimensional electrophoresis and immunoblotting.
As a result, we did not found any expression of NAIF1at RNA or protein level in gastric cancer cell AGS, MKN45, SGC7901or one immortalized gastric mucosa cell line GES-1. When NAIF1was transfected into AGS and MKN45cell, it showed that NAIF1only distributed in the nucleus. Overexpression of NAIF1led to a G1-S arrest in MKN45cells and also decreased the cell migration ability in both AGS and MKN45, with a decrement of3times in AGS or2.8times in MKN45. Immunoblotting result suggested that NAIFl induced cell cycle arrest by down-regulating the expression of CyclinDl. Besides, NAIFl was able to reduce the activity of Erkl/2and JNK with or without stimulation by UV/serum, but had no effect on P38. In addition, NAIF1was able to reduce the expression level of JNK. As a downstream gene of MAPK pathway, the down-regulation of expression of MMP2and MMP9were also observed. Moreover, inhibition of p-FAK was detected in NAIFl-overexpressed cell. Two-dimensional electrophoresis was used to indicate that overexpression of NAIF1had a effect on the protein expression profile in MKN45cells, with up-regulation of5proteins including PSMC2、PSMD13、TXNRD1、TCP1-gamma and NDUSF1, and down-regulation of3protein,14-3-3epsilon, RNH1and APIAOBP. Westernblotting was introduced to vertify the result of Two-dimensional electrophoresis.By using genomics approaches, we also found that155genes showed a>2fold change after overexpressing NAIF1in cell, correlation analysis showed most of which were involed in immune response pathways. These proteomics and genomics data provide new ideas and directions for researching NAIF1in the future.
This is the first time to discover the ability of NAIFl in cell migration and the first time to investigate the relationship between NAIF1and MAPK pathway, as well as CyclinDl and other downstream moleculars of MAPK pathways. This research is an innovation by revealing the functions and molecular mechanisms in which NAIFl was involved, have directive significance for understanding function and molecular mechanism of NAIF1in future, and provide a new target for the therapy of tumor invasion and metastasis.
NAIF1是一个核凋亡诱导因子,前期研究发现NAIF1能够诱导HeLa细胞和MKN45细胞凋亡,凋亡通过线粒体途径发生,涉及到了Caspase9和Caspase3的活化,并且NAIF1在人胃癌组织和癌旁组织中呈现差异表达,癌旁组织高表达,胃癌组织低表达或不表达。但对NAIF1在细胞中的功能研究仅限于此,NAIF1在细胞内还参与了哪些通路、还发挥了哪些作用尚不清楚。
本研究以NAIF1基因和胃癌细胞系为研究对象,采用了激光共聚焦、流式细胞术、transwell、real-time Q PCR、双向电泳、免疫杂交等多种实验技术,对NAIF1基因在胃癌细胞中的表达、分布、功能、功能相关机理和对蛋白表达谱的影响等进行了研究。
我们检测到,在三株胃癌细胞系AGS、MKN45、SGC7901和一株永生化胃粘膜细胞系GES-1中,NAIF1在蛋白水平和RNA水平上均无表达。外源的NAIF1在AGS和MKN45这两株细胞中均只在细胞核内分布。过表达NAIF1能够诱导MKN45细胞产生G0/G1期的周期阻滞,并且抑制了AGS和MKN45细胞的运动能力,细胞迁移率分别下降了3倍和2.8倍。在机制研究中,我们发现NAIF1通过降低CyclinD1的表达诱导了细胞周期阻滞。在无刺激和采用血清/紫外刺激的不同情况下,NAIF1均能够降低AGS和MKN45细胞内Erk1/2>JNK的磷酸化水平,但对p38通路无影响。并且,NAIF1还降低了MKN45细胞内JNK的本底表达水平cMAPK的下游基因中,MMP2、 MMP9的表达降低。我们还发现NAIF1过表达的细胞中FAK-Ser910的磷酸化水平降低。我们推测,NAIF1可能是通过对MAPK通路的调节,来影响其下游Cyclin1、 MMP2、MMP9以及FAK的表达量或活性,进而对细胞周期和细胞的运动能力进行调控。利用蛋白质组学的方法,我们通过双向电泳实验检测到NAIF1基因在MKN45细胞内过表达后上调了5种蛋白PSMC2、PSMD13、TXNRD1、TCP1-gamma和NDUSF1的表达水平,下调了3种蛋白14-3-3epsilon RNH1和APIAOBP的表达水平。Westernblotting实验验证了TXNRD1、TCP1-gamma两种蛋白在NAIF1过表达的MKN45细胞中表达上调,14-3-3epsilon表达下调。利用基因组学的方法,我们还发现当在细胞内过表达NAIF1基因时,155个胞内基因出现了大于2倍的表达量变化,GO分析显示大部分基因参与了免疫反应调节的生物学进程。这一结果为NAIF1基因的研究提供了新的思路和方向。
本研究是首次发现NAIF1通过调节CyclinD1的表达导致了MKN45细胞出现周期阻滞,并首次发现NAIF1通过对MAPK通路及其下游基因的调控来影响细胞的运动能力。也是首次通过蛋白质组学的方法对NAIF1基因所引起的细胞蛋白谱的表达变化做出了研究。本文的研究结果具有创新意义,揭示了NAIF1基因在细胞内涉及的新的功能和新的分子机制,对于今后理解并研究NAIF1基因的功能和作用机制具有指导意义,同时对于胃癌浸润转移的治疗也提供了新的分子靶点。
As a common digestive tract cancer, the incidence of gastric cancer occupied the fourth place of all human cancers with a lethality rate of70%, which is much higher than other common human cancers. High morbidity and high mortality rate of gastric cancer has a serious impact on human health. Tumor invasion and metastasis are the main reasons for the bad prognosis of patients and lead to high lethality rate, therefore, researching the related molecules and pathways of invasion and metastasis in gastric cancer cell will not only help us with a better understanding of the molecular mechanisms, but also provide new markers and targets for gastric cancer diagnosis and therapy.
NAIF1is a nuclear apoptosis-inducing factor. Previous findings showed that NAIF1was able to induce apoptosis in HeLa cells and MKN45cells through mitochondrial pathway, and these events involved the activation of Caspase9and Caspase3, in addition, NAIF1showed a different expression between human gastric cancer tissues and adjacent tissues. However, whether NAIF1was involved in other cell functions and pathways was still unknown.
In this study, we focus on the functions and mechanisms of NAIF1in gastric cancer cells. A variety of experimental techniques were employed including confocal scanning, flow cytometry, transwell, real-time Q PCR, two-dimensional electrophoresis and immunoblotting.
As a result, we did not found any expression of NAIF1at RNA or protein level in gastric cancer cell AGS, MKN45, SGC7901or one immortalized gastric mucosa cell line GES-1. When NAIF1was transfected into AGS and MKN45cell, it showed that NAIF1only distributed in the nucleus. Overexpression of NAIF1led to a G1-S arrest in MKN45cells and also decreased the cell migration ability in both AGS and MKN45, with a decrement of3times in AGS or2.8times in MKN45. Immunoblotting result suggested that NAIFl induced cell cycle arrest by down-regulating the expression of CyclinDl. Besides, NAIFl was able to reduce the activity of Erkl/2and JNK with or without stimulation by UV/serum, but had no effect on P38. In addition, NAIF1was able to reduce the expression level of JNK. As a downstream gene of MAPK pathway, the down-regulation of expression of MMP2and MMP9were also observed. Moreover, inhibition of p-FAK was detected in NAIFl-overexpressed cell. Two-dimensional electrophoresis was used to indicate that overexpression of NAIF1had a effect on the protein expression profile in MKN45cells, with up-regulation of5proteins including PSMC2、PSMD13、TXNRD1、TCP1-gamma and NDUSF1, and down-regulation of3protein,14-3-3epsilon, RNH1and APIAOBP. Westernblotting was introduced to vertify the result of Two-dimensional electrophoresis.By using genomics approaches, we also found that155genes showed a>2fold change after overexpressing NAIF1in cell, correlation analysis showed most of which were involed in immune response pathways. These proteomics and genomics data provide new ideas and directions for researching NAIF1in the future.
This is the first time to discover the ability of NAIFl in cell migration and the first time to investigate the relationship between NAIF1and MAPK pathway, as well as CyclinDl and other downstream moleculars of MAPK pathways. This research is an innovation by revealing the functions and molecular mechanisms in which NAIFl was involved, have directive significance for understanding function and molecular mechanism of NAIF1in future, and provide a new target for the therapy of tumor invasion and metastasis.
引文
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